N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase

ABSTRACT

Novel substituted benzamide based inhibitors, their use in therapy, pharmaceutical compositions comprising the compounds, the use of said compounds in the manufacture of medicaments, and therapeutic methods comprising the administration of said compounds are described. The present compounds modulate the activity of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and are accordingly useful in the treatment of diseases in which such a modulation is beneficial, such as the metabolic syndrome.

The present invention relates to novel substituted benzamide basedinhibitors, to their use in therapy, to pharmaceutical compositionscomprising the compounds, to the use of said compounds in themanufacture of medicaments, and to therapeutic methods comprising theadministration of said compounds. The present compounds modulate theactivity of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and areaccordingly useful in the treatment of diseases in which such amodulation is beneficial, such as the metabolic syndrome.

BACKGROUND OF THE INVENTION

The metabolic syndrome is a major global health problem. In the US, theprevalence in the adult population is currently estimated to beapproximately 25%, and it continues to increase both in the US andworldwide. The metabolic syndrome is characterised by a combination ofinsulin resistance, dyslipidemia, obesity and hypertension leading toincreased morbidity and mortality of cardiovascular diseases. Peoplewith the metabolic syndrome are at increased risk of developing franktype 2 diabetes, the prevalence of which is equally escalating.

In type 2 diabetes, obesity and dyslipidemia are also highly prevalentand around 70% of people with type 2 diabetes additionally havehypertension once again leading to increased mortality of cardiovasculardiseases.

In the clinical setting, it has long been known that glucocorticoids areable to induce all of the cardinal features of the metabolic syndromeand type 2 diabetes.

11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyses the localgeneration of active glucocorticoid in several tissues and organsincluding predominantly the liver and adipose tissue, but also e.g.skeletal muscle, bone, pancreas, endothelium, ocular tissue and certainparts of the central nervous system. Thus, 11βHSD1 serves as a localregulator of glucocorticoid actions in the tissues and organs where itis expressed (Tannin et al., J. Biol. Chem., 266, 16653 (1991); Bujalskaet al., Endocrinology, 140, 3188 (1999); Whorwood et al., J ClinEndocrinol Metab., 86, 2296 (2001); Cooper et al., Bone, 27, 375 (2000);Davani et al., J. Biol. Chem., 275, 34841 (2000); Brem et al.,Hypertension, 31, 459 (1998); Rauz et al., Invest. Ophthalmol. Vis.Sci., 42, 2037 (2001); Moisan et al., Endocrinology, 127, 1450 (1990)).

The role of 11βHSD1 in the metabolic syndrome and type 2 diabetes issupported by several lines of evidence. In humans, treatment with thenon-specific 11βHSD1 inhibitor carbon-oxolone improves insulinsensitivity in lean healthy volunteers and people with type 2 diabetes.Likewise, 11βHSD1 knock-out mice are resistant to insulin resistanceinduced by obesity and stress. Additionally, the knock-out mice presentwith an anti-atherogenic lipid profile of decreased VLDL triglyceridesand increased HDL-cholesterol. Conversely, mice that overexpress 11βHSD1in adipocytes develop insulin resistance, hyperlipidemia and visceralobesity, a phenotype that resembles the human metabolic syndrome(Andrews et al., J. Clin. Endocrinol. Metab., 88, 285 (2003); Walker etal., J. Clin. Endocrinol. Metab., 80, 3155 (1995); Morton et al., J.Biol. Chem., 276, 41293 (2001); Kotelevtsev et al., Proc. Natl. Acad.Sci. USA, 94, 14924 (1997); Masuzaki et al., Science, 294, 2166 (2001)).

The more mechanistic aspects of 11βHSD1 modulation and therebymodulation of intracellular levels of active glucocorticoid have beeninvestigated in several rodent models and different cellular systems.11βHSD1 promotes the features of the metabolic syndrome by increasinghepatic expression of the rate-limiting enzymes in gluconeogenesis,namely phosphoenolpyruvate carboxykinase and glucose-6-phosphatase,promoting the differentiation of preadipocytes into adipocytes thusfacilitating obesity, directly and indirectly stimulating hepatic VLDLsecretion, decreasing hepatic LDL uptake and increasing vesselcontractility (Kotelevtsev et al., Proc. Natl. Acad. Sci. USA, 94, 14924(1997); Morton et al., J. Biol. Chem. 276, 41293 (2001); Bujalska etal., Endocrinology, 140, 3188 (1999); Souness et al., Steroids, 67, 195(2002), Brindley & Salter, Prog. Lipid Res., 30, 349 (1991)).

WO 01/90090, WO 01/90091, WO 01/90092, WO 01/90093 and WO 01/90094discloses various thiazol-sulfonamides as inhibitors of the human11β-hydroxysteroid dehydrogenase type 1 enzyme, and further states thatsaid compounds may be useful in treating diabetes, obesity, glaucoma,osteoporosis, cognitive disorders, immune disorders and depression. WO2004/089470 discloses various substituted amides and the use thereof forstimulating 11β-hydroxysteroid dehydrogenase type 1. WO 2004/089415 andWO 2004/089416 discloses various combination therapies using an11β-hydroxysteroid dehydrogenase type 1 inhibitor and respectively aglucocorticoid receptor agonist or an antihypertensive agent.

We have now found substituted benzamide based inhibitors that modulatethe activity of 11βHSD1 leading to altered intracellular concentrationsof active glucocorticoid. More specifically, the present compoundsinhibit the activity of 11βHSD1 leading to decreased intracellularconcentrations of active glucocorticoid. Thus, the present compounds canbe used to treat disorders where a decreased level of activeintracellular glucocorticoid is desirable, such as e.g. the metabolicsyndrome, type 2 diabetes, impaired glucose tolerance (IGT), impairedfasting glucose (IFG), dyslipidemia, obesity, hypertension, diabeticlate complications, cardiovascular diseases, arteriosclerosis,atherosclerosis, myopathy, muscle wasting, osteoporosis,neurodegenerative and psychiatric disorders, and adverse effects oftreatment or therapy with glucocorticoid receptor agonists.

One object of the present invention is to provide compounds,pharmaceutical compositions and use of compounds that modulate theactivity of 11βHSD1.

DEFINITIONS

The term “monovalent radical” shall mean a chemical group attached via asingle bond.

The term “halogen” or “halo” means fluorine, chlorine, bromine oriodine.

The term “hydroxy” shall mean the radical —OH.

The term “carboxy” shall mean the radical —(C═O)OH.

The term “C₁-C₆alkyl” as used herein represents a saturated, branched orstraight hydrocarbon group having from 1 to 6 carbon atoms, e.g.C₁-C₂alkyl, C₁-C₃alkyl, C₁-C₋₄ alkyl, C₁-C₆alkyl, C₂-C₆alkyl,C₃-C₆alkyl, and the like. Representative examples are methyl, ethyl,propyl (e.g. prop-1-yl, prop-2-yl (or iso-propyl)), butyl (e.g.2-methylprop-2-yl (or tert-butyl), but-1-yl, but-2-yl), pentyl (e.g.pent-1-yl, pent-2-yl, pent-3-yl), 2-methylbut-1-yl, 3-methylbut-1-yl,hexyl (e.g. hex-1-yl), and the like. The term “C₁-C₄alkyl” as usedherein represents a saturated, branched or straight hydrocarbon grouphaving from 1 to 4 carbon atoms, e.g. C₁-C₂alkyl, C₁-C₃alkyl, C₁-C₋₄alkyl, and the like. Representative examples are methyl, ethyl, propyl(e.g. prop-1-yl, prop-2-yl (or iso-propyl)), butyl (e.g.2-methylprop-2-yl (or tert-butyl), but-1-yl, but-2-yl), and the like.

The term “bridge” as used herein represents a connection in a saturatedor partly saturated ring between two atoms of such ring that are notneighbors through a chain of 1 to 3 atoms selected from carbon,nitrogen, oxygen and sulfur. Representative examples of such connectingchains are —CH₂—, —CH₂CH₂—, —CH₂NHCH₂—, —CH₂CH₂CH₂—, —CH₂OCH₂—, and thelike.

In one embodiment according to the invention, the connecting chain isselected from the group consisting of —CH₂—, —CH₂CH₂—, or —CH₂OCH₂—.

The term “spiro atom” as used herein represents a carbon atom in asaturated or partly saturated ring that connects both ends of a chain of3 to 7 atoms selected from carbon, nitrogen, oxygen and sulfur.Representative examples are —(CH₂)₅—, —(CH₂)₃—, —(CH₂)₄—, —CH₂NHCH₂CH₂—,—CH₂CH₂NHCH₂CH₂—, —CH₂NHCH₂CH₂CH₂—, —CH₂CH₂OCH₂—, —OCH₂CH₂O—, and thelike.

The term “C₃-C₁₀cycloalkyl” as used herein represents a saturatedmonocyclic carbocyclic ring having from 3 to 10 carbon atoms, e.g.C₃₋₆-alkyl, C₃₋₁₀-alkyl, and the like.

Representative examples are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, and the like. C₃-C₁₀cycloalkyl isalso intended to represent a saturated bicyclic carbocyclic ring havingfrom 4 to 10 carbon atoms. Representative examples aredecahydro-naphthalenyl, bicyclo[3.3.0]octanyl, and the like.C₃-C₁₀cycloalkyl is also intended to represent a saturated carbocyclicring having from 3 to 10 carbon atoms and containing one or two carbonbridges. Representative examples are adamantyl, norbornanyl,nortricyclyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl,tricyclo[5.2.1.0/2,6]decanyl, bicyclo[2.2.1]-heptyl, and the like.C₃-C₁₀cycloalkyl is also intended to represent a saturated carbocyclicring having from 3 to 10 carbon atoms and containing one or more spiroatoms. Representative examples are spiro[2.5]octanyl, spiro[4.5]decanyl,and the like.

The term “aryl” as used herein is intended to include monocyclic,bicyclic or polycyclic carbocyclic aromatic rings. Representativeexamples are phenyl, naphthyl (e.g. naphth-1-yl, naphth-2-yl), anthryl(e.g. anthr-1-yl, anthr-9-yl), phenanthryl (e.g. phenanthr-1-yl,phenanthr-9-yl), and the like. Aryl is also intended to includemonocyclic, bicyclic or polycyclic carbocyclic aromatic ringssubstituted with carbocyclic aromatic rings. Representative examples arebiphenyl (e.g. biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl),phenylnaphthyl (e.g. 1-phenylnaphth-2-yl, 2-phenylnaphth-1-yl), and thelike. Aryl is also intended to include partially saturated bicyclic orpolycyclic carbocyclic rings with at least one unsaturated moiety (e.g.a benzo moiety). Representative examples are, indanyl (e.g. indan-1-yl,indan-5-yl), indenyl (e.g. inden-1-yl, inden-5-yl),1,2,3,4-tetrahydronaphthyl (e.g. 1,2,3,4-tetrahydronaphth-1-yl,1,2,3,4-tetrahydronaphth-2-yl, 1,2,3,4-tetrahydronaphth-6-yl),1,2-dihydronaphthyl (e.g. 1,2-dihydronaphth-1-yl,1,2-dihydronaphth-4-yl, 1,2-dihydronaphth-6-yl), fluorenyl (e.g.fluoren-1-yl, fluoren-4-yl, fluoren-9-yl), and the like. Aryl is alsointended to include partially saturated bicyclic or polycycliccarbocyclic aromatic rings containing one or two bridges. Representativeexamples are, benzonorbornyl (e.g. benzonorborn-3-yl,benzonorborn-6-yl), 1,4-ethano-1,2,3,4-tetrahydronapthyl (e.g.1,4-ethano-1,2,3,4-tetrahydronapth-2-yl,1,4-ethano-1,2,3,4-tetrahydronapth-10-yl), and the like. Aryl is alsointended to include partially saturated bicyclic or polycycliccarbocyclic aromatic rings containing one or more spiro atoms.Representative examples are spiro[cyclopentane-1,1′-indane]-4-yl,spiro[cyclopentane-1,1′-indene]-4-yl,spiro[piperidine-4,1′-indane]-1-yl, spiro[piperidine-3,2′-indane]-1-yl,spiro[piperidine-4,2′-indane]-1-yl, spiro[piperidine-4,1′-indane]-3′-yl,spiro[pyrrolidine-3,2′-indane]-1-yl,spiro[pyrrolidine-3,1′-(3′,4′-dihydronaphthalene)]-1-yl,spiro[piperidine-3,1′-(3′,4′-dihydronaphthalene)]-1-yl,spiro[piperidine-4,1′-(3′,4′-dihydronaphthalene)]-1-yl,spiro[imidazolidine-4,2′-indane]-1-yl,spiro[piperidine-4,1′-indene]-1-yl, and the like.

The term “C₃-C₁₀heterocyclyl” as used herein represents a saturated 3 to10 membered monocyclic ring, containing one or more heteroatoms selectedfrom nitrogen, oxygen, sulfur, S(═O) and S(═O)₂. Representative examplesare aziridinyl (e.g. aziridin-1-yl), azetidinyl (e.g. azetidin-1-yl,azetidin-3-yl), oxetanyl, pyrrolidinyl (e.g. pyrrolidin-1-yl,pyrrolidin-2-yl, pyrrolidin-3-yl), imidazolidinyl (e.g.imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl), oxazolidinyl(e.g. oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl), thiazolidinyl(e.g. thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl),isothiazolidinyl, piperidinyl (e.g. piperidin-1-yl, piperidin-2-yl,piperidin-3-yl, piperidin-4-yl), homopiperidinyl (e.g.homopiperidin-1-yl, homopiperidin-2-yl, homopiperidin-3-yl,homopiperidin-4-yl), piperazinyl (e.g. piperazin-1-yl, piperazin-2-yl),morpholinyl (e.g. morpholin-2-yl, morpholin-3-yl, morpholin-4-yl),thiomorpholinyl (e.g. thiomorpholin-2-yl, thiomorpholin-3-yl,thiomorpholin-4-yl), 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl,tetrahydrofuranyl (e.g. tetrahydrofuran-2-yl, tetrahydrofuran-3-yl),tetrahydrothienyl, tetrahydro-1,1-dioxothienyl, tetrahydropyranyl (e.g.2-tetrahydropyranyl), tetrahydrothiopyranyl (e.g.2-tetrahydrothiopyranyl), 1,4-dioxanyl, 1,3-dioxanyl, and the like.C₃-C₁₀heterocyclyl is also intended to represent a saturated 6 to 10membered bicyclic ring containing one or more heteroatoms selected fromnitrogen, oxygen, sulfur, S(═O) and S(═O)₂. Representative examples areoctahydroindolyl (e.g. octahydroindol-1-yl, octahydroindol-2-yl,octahydroindol-3-yl, octahydroindol-5-yl), decahydroquinolinyl (e.g.decahydroquinolin-1-yl, decahydroquinolin-2-yl, decahydroquinolin-3-yl,decahydroquinolin-4-yl, decahydroquinolin-6-yl), decahydroquinoxalinyl(e.g. decahydroquinoxalin-1-yl, decahydroquinoxalin-2-yl,decahydroquinoxalin-6-yl) and the like. C₃-C₁₀heterocyclyl is alsointended to represent a saturated 6 to 10 membered ring containing oneor more heteroatoms selected from nitrogen, oxygen, sulfur, S(═O) andS(═O)₂ and having one or two bridges. Representative examples are3-azabicyclo-[3.2.2]nonyl, 2-azabicyclo[2.2.1]heptyl,3-azabicyclo[3.1.0]hexyl, 2,5-diazabicyclo-[2.2.1]heptyl, atropinyl,tropinyl, quinuclidinyl, 1,4-diazabicyclo[2.2.2]octanyl, and the like.C₃-C₁₀heterocyclyl is also intended to represent a 6 to 10 memberedsaturated ring containing one or more heteroatoms selected fromnitrogen, oxygen, sulfur, S(═O) and S(═O)₂ and containing one or morespiro atoms. Representative examples are 1,4-dioxaspiro[4.5]decanyl(e.g. 1,4-dioxaspiro[4.5]decan-2-yl, 1,4-dioxaspiro[4.5]decan-7-yl),1,4-dioxa-8-azaspiro[4.5]decanyl (e.g.1,4-dioxa-8-azaspiro[4.5]decan-2-yl,1,4-dioxa-8-azaspiro[4.5]decan-8-yl), 8-azaspiro[4.5]decanyl (e.g.8-azaspiro[4.5]decan-1-yl, 8-azaspiro[4.5]decan-8-yl),2-azaspiro[5.5]undecanyl (e.g. 2-azaspiro[5.5]undecan-2-yl),2,8-diazaspiro[4.5]decanyl (e.g. 2,8-diazaspiro[4.5]decan-2-yl,2,8-diazaspiro[4.5]decan-8-yl), 2,8-diazaspiro[5.5]undecanyl (e.g.2,8-diazaspiro[5.5]undecan-2-yl), 1,3,8-triazaspiro[4.5]decanyl (e.g.1,3,8-triazaspiro[4.5]decan-1-yl, 1,3,8-triazaspiro[4.5]decan-3-yl,1,3,8-triazaspiro[4.5]decan-8-yl), and the like.

The term “heteroaryl” as used herein is intended to include monocyclicheterocyclic aromatic rings containing one or more heteroatoms selectedfrom nitrogen, oxygen, sulfur, SO and S(═O)₂. Representative examplesare pyrrolyl (e.g. pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl), furanyl (e.g.furan-2-yl, furan-3-yl), thienyl (e.g. thien-2-yl, thien-3-yl), oxazolyl(e.g. oxazol-2-yl, oxazol-4-yl, oxazol-5-yl), thiazolyl (e.g.thiazol-2-yl, thiazol-4-yl, thiazol-5-yl), imidazolyl (e.g.imidazol-2-yl, imidazol-4-yl, imidazol-5-yl), pyrazolyl (e.g.pyrazol-1-yl, pyrazol-3-yl, pyrazol-5-yl), isoxazolyl (e.g.isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl), isothiazolyl (e.g.isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl), 1,2,3-triazolyl(e.g. 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl),1,2,4-triazolyl (e.g. 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl,1,2,4-triazol-5-yl), 1,2,3-oxadiazolyl (e.g. 1,2,3-oxadiazol-4-yl,1,2,3-oxadiazol-5-yl), 1,2,4-oxadiazolyl (e.g. 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl), 1,2,5-oxadiazolyl (e.g. 1,2,5-oxadiazol-3-yl,1,2,5-oxadiazol-4-yl), 1,3,4-oxadiazolyl (e.g. 1,3,4-oxadiazol-2-yl,1,3,4-oxadiazol-5-yl), 1,2,3-thiadiazolyl (e.g. 1,2,3-thiadiazol-4-yl,1,2,3-thiadiazol-5-yl), 1,2,4-thiadiazolyl (e.g. 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl), 1,2,5-thiadiazolyl (e.g. 1,2,5-thiadiazol-3-yl,1,2,5-thiadiazol-4-yl), 1,3,4-thiadiazolyl (e.g. 1,3,4-thiadiazol-2-yl,1,3,4-thiadiazol-5-yl), tetrazolyl (e.g. tetrazol-1-yl, tetrazol-5-yl),pyranyl (e.g. pyran-2-yl), pyridinyl (e.g. pyridine-2-yl, pyridine-3-yl,pyridine-4-yl), pyridazinyl (e.g. pyridazin-2-yl, pyridazin-3-yl),pyrimidinyl (e.g. pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl),pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,thiadiazinyl, azepinyl, azecinyl, and the like. Heteroaryl is alsointended to include bicyclic heterocyclic aromatic rings containing oneor more heteroatoms selected from nitrogen, oxygen, sulfur, S(═O) andS(═O)₂. Representative examples are indolyl (e.g. indol-1-yl,indol-2-yl, indol-3-yl, indol-5-yl), isoindolyl, benzofuranyl (e.g.benzo[b]furan-2-yl, benzo[b]furan-3-yl, benzo[b]furan-5-yl,benzo[c]furan-2-yl, benzo[c]furan-3-yl, benzo[c]furan-5-yl),benzothienyl (e.g. benzo[b]thien-2-yl, benzo[b]thien-3-yl,benzo[b]thien-5-yl, benzo[c]thien-2-yl, benzo[c]thien-3-yl,benzo[c]thien-5-yl), indazolyl (e.g. indazol-1-yl, indazol-3-yl,indazol-5-yl), indolizinyl (e.g. indolizin-1-yl, indolizin-3-yl),benzopyranyl (e.g. benzo[b]pyran-3-yl, benzo[b]pyran-6-yl,benzo[c]pyran-1-yl, benzo[c]pyran-7-yl), benzimidazolyl (e.g.benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl), benzothiazolyl(e.g. benzothiazol-2-yl, benzothiazol-5-yl), benzisothiazolyl,benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzotriazolyl,naphthyridinyl (e.g. 1,8-naphthyridin-2-yl, 1,7-naphthyridin-2-yl,1,6-naphthyridin-2-yl), phthalazinyl (e.g. phthalazin-1-yl,phthalazin-5-yl), pteridinyl, purinyl (e.g. purin-2-yl, purin-6-yl,purin-7-yl, purin-8-yl, purin-9-yl), quinazolinyl (e.g. quinazolin-2-yl,quinazolin-4-yl, quinazolin-6-yl), cinnolinyl, quinoliny (e.g.quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl),isoquinolinyl (e.g. isoquinolin-1-yl, isoquinolin-3-yl,isoquinolin-4-yl), quinoxalinyl (e.g. quinoxalin-2-yl, quinoxalin-5-yl),pyrrolopyridinyl (e.g. pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl,pyrrolo[3,2-c]pyridinyl), furopyridinyl (e.g. furo[2,3-b]pyridinyl,furo[2,3-c]pyridinyl, furo[3,2-c]pyridinyl), thienopyridinyl (e.g.thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl),imidazopyridinyl (e.g. imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl,imidazo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl), imidazopyrimidinyl(e.g. imidazo[1,2-a]pyrimidinyl, imidazo[3,4-a]pyrimidinyl),pyrazolopyridinyl (e.g. pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[1,5-a]pyridinyl), pyrazolopyrimidinyl(e.g. pyrazolo[1,5-a]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl),thiazolopyridinyl (e.g. thiazolo[3,2-d]pyridinyl), thiazolopyrimidinyl(e.g. thiazolo[5,4-d]pyrimidinyl), imdazothiazolyl (e.g.imidazo[2,1-b]thiazolyl), triazolopyridinyl (e.g.triazolo[4,5-b]pyridinyl), triazolopyrimidinyl (e.g. 8-azapurinyl), andthe like. Heteroaryl is also intended to include polycyclic heterocyclicaromatic rings containing one or more heteroatoms selected fromnitrogen, oxygen, sulfur, S(═O) and S(═O)₂. Representative examples arecarbazolyl (e.g. carbazol-2-yl, carbazol-3-yl, carbazol-9-yl),phenoxazinyl (e.g. phenoxazin-10-yl), phenazinyl (e.g. phenazin-5-yl),acridinyl (e.g. acridin-9-yl, acridin-10-yl), phenothiazinyl (e.g.phenothiazin-10-yl), carbolinyl (e.g. pyrido[3,4-b]indol-1-yl,pyrido[3,4-b]indol-3-yl), phenanthrolinyl (e.g. phenanthrolin-5-yl), andthe like. Heteroaryl is also intended to include partially saturatedmonocyclic, bicyclic or polycyclic heterocyclic rings containing one ormore heteroatoms selected from nitrogen, oxygen, sulfur, S(═O) andS(═O)₂. Representative examples are pyrrolinyl, pyrazolinyl,imidazolinyl (e.g. 4,5-dihydroimidazol-2-yl, 4,5-dihydroimidazol-1-yl),indolinyl (e.g. 2,3-dihydroindol-1-yl, 2,3-dihydroindol-5-yl),dihydrobenzofuranyl (e.g. 2,3-dihydrobenzo[b]furan-2-yl,2,3-dihydrobenzo[b]furan-4-yl), dihydrobenzothienyl (e.g.2,3-dihydrobenzo[b]thien-2-yl, 2,3-dihydrobenzo[b]thien-5-yl),4,5,6,7-tetrahydrobenzo[b]furan-5-yl), dihydrobenzopyranyl (e.g.3,4-dihydrobenzo[b]pyran-3-yl, 3,4-dihydrobenzo[b]pyran-6-yl,3,4-dihydrobenzo-[c]pyran-1-yl, dihydrobenzo[c]pyran-7-yl), oxazolinyl(e.g. 4,5-dihydrooxazol-2-yl, 4,5-dihydrooxazol-4-yl,4,5-dihydrooxazol-5-yl), isoxazolinyl, oxazepinyl, tetrahydroindazolyl(e.g. 4,5,6,7-tetrahydroindazol-1-yl, 4,5,6,7-tetrahydroindazol-3-yl,4,5,6,7-tetrahydroindazol-4-yl, 4,5,6,7-tetrahydroindazol-6-yl),tetrahydrobenzimidazolyl (e.g. 4,5,6,7-tetrahydrobenzimidazol-1-yl,4,5,6,7-tetrahydrobenzimidazol-5-yl), tetrahydroimidazo[4,5-c]pyridyl(e.g. 4,5,6,7-tetrahydroimidazo[4,5-c]pyrid-1-yl,4,5,6,7-tetrahydroimidazo[4,5-c]pyrid-5-yl,4,5,6,7-tetrahydroimidazo[4,5-c]pyrid-6-yl), tetrahydroquinolinyl (e.g.1,2,3,4-tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinolinyl),tetrahydroisoquinolinyl (e.g. 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinoxalinyl (e.g.1,2,3,4-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinoxalinyl), and thelike. Heteroaryl is also intended to include partially saturatedbicyclic or polycyclic heterocyclic rings containing one or more spiroatoms. Representative examples arespiro[isoquinoline-3,1′-cyclohexan]-1-yl,spiro[piperidine-4,1′-benzo[c]thiophen]-1-yl,spiro[piperidine-4,1′-benzo[c]furan]-1-yl,spiro[piperidine-4,3′-benzo[b]furan]-1-yl,spiro[piperidine-4,3′-coumarin]-1-yl, and the like.

The term “monocyclic heteroaryl” as used herein is intended to includemonocyclic heterocyclic aromatic rings as defined above.

The term “bicyclic heteroaryl” as used herein is intended to includebicyclic heterocyclic aromatic rings as defined above.

The term “4 to 6 membered ring” as used herein represents a saturated 3to 6 membered monocyclic ring, containing one nitrogen and it mightcontain a further heteroatom selected from oxygen, sulfur, S(═O) andS(═O)₂ and it is intended to include pyrrolidinyl (e.g. pyrrolidin-1-yl,pyrrolidin-2-yl, pyrrolidin-3-yl), piperidinyl (e.g. piperidin-1-yl,piperidin-2-yl, piperidin-3-yl, piperidin-4-yl), morpholinyl (e.g.morpholin-2-yl, morpholin-3-yl, morpholin-4-yl), thiomorpholinyl (e.g.thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl),1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, aziridinyl (e.g.aziridin-1-yl), azetidinyl (e.g. azetidin-1-yl, azetidin-3-yl),azetidine and the like.

The term C₁-C₄alkylcarbonyl as used herein refers to the radical C₁-C₋₄alkyl-C(═O)—.

Certain of the defined terms may occur more than once in the structuralformulae, and upon such occurrence each term shall be definedindependently of the other.

Certain of the defined terms may occur in combinations, and it is to beunderstood that the first mentioned radical is a substituent on thesubsequently mentioned radical, where the point of substitution, i.e.the point of attachment to another part of the molecule, is on the lastmentioned of the radicals.

The term “treatment” is defined as the management and care of a patientfor the purpose of combating or alleviating the disease, condition ordisorder, and the term includes the administration of the activecompound to prevent the onset of the symptoms or complications, oralleviating the symptoms or complications, or eliminating the disease,condition, or disorder.

The term “pharmaceutically acceptable” is defined as being suitable foradministration to humans without adverse events.

The term “prodrug” is defined as a chemically modified form of theactive drug, said prodrug being administered to the patient andsubsequently being converted to the active drug. Techniques fordevelopment of prodrugs are well known in the art.

SUMMARY OF THE INVENTION

In one aspect of the invention substituted benzamide based inhibitorsthat modulate the activity of 11βHSD1 leading to altered intracellularconcentrations of active glucocorticoid are provided. More specifically,the present compounds inhibit the activity of 11βHSD1 leading todecreased intracellular concentrations of active glucocorticoid. Thus,the present compounds can be used to treat disorders where a decreasedlevel of active intracellular glucocorticoid is desirable, such as e.g.the metabolic syndrome, type 2 diabetes, impaired glucose tolerance(IGT), impaired fasting glucose (IFG), dyslipidemia, obesity,hypertension, diabetic late complications, cardiovascular diseases,arteriosclerosis, atherosclerosis, myopathy, muscle wasting,osteoporosis, neurodegenerative and psychiatric disorders, and adverseeffects of treatment or therapy with glucocorticoid receptor agonists.

One object of the present invention is to provide compounds,pharmaceutical compositions and use of compounds that modulate theactivity of 11βHSD1.

The present invention furthermore relates to the use in therapy of thecompounds according to the invention, to pharmaceutical compositionscomprising the compounds, to the use of said compounds in themanufacture of medicaments, and to therapeutic methods comprising theadministration of said compounds.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides for a compound of the general formula (I):

wherein R¹ is selected from the group consisting of hydrogen, methyl,ethyl, isopropyl and cyclopropyl and R² is selected from the groupconsisting of a monovalent radical having one of the following formulae,wherein the symbol * denotes the point of attachment:

or R¹ and R² together with the nitrogen to which they are attached isselected from the group consisting of one of the following formulaewherein the symbol * denotes the point of attachment:

Q is selected is selected from the group consisting of hydroxy, carboxy,—S(═O)₂R⁶, and S(═O)₂NH₂;P is selected from the group consisting of —S(═O)₂R⁶, carboxy and—S(═O)₂NH₂;R⁶ is selected from the group consisting of C₁-C₄alkyl, phenyl, pyridineand C₃-C₁₀cycloalkyl, wherein said C₁-C₄alkyl, phenyl, pyridine andC₃-C₁₀cycloalkyl are optionally substituted with one or twoindependently selected R⁷;R⁷ is selected from the group consisting of hydrogen, methyl, ethyl,cyclopropyl, —O—CH₃, —O-cyclopropyl, —O-isopropyl, hydroxy, and halogen,wherein said methyl, ethyl, cyclopropyl, —O—CH₃, —O-cyclopropyl and—O-isopropyl is optionally substituted with one substituent selectedfrom the group consisting of hydroxy and halogen;R⁴ is selected from the group consisting of hydrogen, C₁-C₄alkylsubstituted with R¹² and R¹³, —O—(C₁-C₄alkyl) substituted with R¹² andR¹³, trifluoromethyl, —CN, halogen, —S(═O)₂methyl, —S(═O)₂ethyl,—S(═O)₂cyclopropyl, —S(═O)₂NR¹⁰R¹¹ and —C(═O)NR¹⁰R¹¹;R⁹⁵ is selected from the group consisting of C₁-C₆alkyl, phenyl,pyridine, pyrimidine, cyclopropyl, cyclobutyl and cyclohexyl, whereinsaid C₁-C₆alkyl, phenyl, pyridine, pyrimidine, cyclopropyl, cyclobutyland cyclohexyl are optionally substituted with one or two independentlyselected R⁹⁶;R⁹⁶ is selected from the group consisting of halogen, hydroxy, oxo,trifluoromethyl, C₁-C₆alkyl, and —S(═O)₂methyl;R⁹⁷ is selected from the group consisting of hydrogen and C₁-C₆alkyl;R¹² and R¹³ are each independently selected from the group consisting ofhydrogen, —O—(C₁-C₄alkyl), halogen, carboxy and hydroxy;R⁵ is selected from the group consisting of hydrogen, C₁-C₄alkylsubstituted with R¹⁶, trifluoromethyl, —CN, halogen, C₁-C₄alkylcarbonylsubstituted with R¹⁸, —S(═O)₂R¹⁷, —S(═O)₂NR¹⁴R¹⁵, and —S—R¹⁷;R¹⁰ and R¹¹ are each independently selected from the group consisting ofhydrogen, and C₁-C₄alkyl; or R¹⁰ and R¹¹ together with the nitrogen towhich they are attached form a 4 to 6 membered ring, wherein saidC₁-C₄alkyl and each carbon atom in said 4 to 6 membered ring optionallyis substituted with one or two substituents independently selected fromthe group consisting of hydroxy and halogen;R¹⁴ and R¹⁵ are each independently selected from the group consisting ofhydrogen, and C₁-C₄alkyl; or R¹⁴ and R¹⁵ together with the nitrogen towhich they are attached form a 4 to 6 membered ring, wherein saidC₁-C₄alkyl and each carbon atom in said 4 to 6 membered ring optionallyis substituted with one or two substituents independently selected fromthe group consisting of hydroxy and halogen;R¹⁶ and R¹⁸ are each independently selected from the group consisting ofhydrogen, —O-methyl, methyl, cyclopropyl, halogen, —S(═O)₂-methyl,—S(═O)₂-ethyl, —C(═O)NH₂, —C(═O)N—CH₃CH₃, carboxy, and hydroxy;R¹⁷ is selected from the group consisting of hydrogen and C₁-C₆alkyl,wherein said C₁-C₆alkyl is optionally substituted with one or twosubstituents selected from the group consisting of hydroxy and halogen;Y is selected from the group consisting of —X¹—X²—X³—R³, —X¹⁰,—CR⁷²R⁷³—O—CR⁷⁰R⁷¹—R³, —CR⁷²R⁷³—S—CR⁷⁰R⁷¹—R³,—CR⁷²R⁷³—S(═O)₂—CR⁷⁰R⁷¹—R³, —CR⁷²R⁷³—NR²⁵—S(═O)₂—R³,—CR⁷²R⁷³—CR⁷⁰R⁷¹—S(═O)₂—R³, —CR⁷²R⁷³—CR⁷⁰R⁷¹—O—R³,—CR⁷²R⁷³—CR⁷⁰R⁷¹—S—R³, —CR⁷²R⁷³—CR⁷⁰R⁷¹—NR²⁵—R³, —O—CR⁴⁴R⁴⁵—S(═O)₂—R³,—CR⁷²R⁷³—O—R³, —CR⁷²R⁷³—S—R³, —CR⁷²R⁷³—S(═O)₂—R³, —CR⁷²R⁷³—NR²⁵—R³,—CR⁷²R⁷³—S(═O)₂—R³, —O—R¹⁰³, —O—CR⁴⁴R⁴⁵, —O—CR⁴⁴R⁴⁵—R¹⁰³,—CR⁷²R⁷³—CR⁴⁴R⁴⁵—R¹⁰³, —O—CR⁴⁴R⁴⁵—CR⁷⁰R⁷¹—R¹⁰³,—CR⁷²R⁷³—CR⁴⁴R⁴⁵—CR⁷⁰R⁷¹—R¹⁰³, and —CH₂—R¹⁰³;X¹ is selected from the group consisting of —S—, —S(═O)—, and —S(═O)₂—;X² is absent or is selected from the group consisting of —O—, —CR⁴⁴R⁴⁵—,—S—, —S(═O)—, —S(═O)₂—and —NR²⁵—;X³ is absent or is selected from the group consisting of —O—, —CR⁷⁰R⁷¹—,—S—, —S(═O)—, —S(═O)₂—, and —NR¹²⁵—;X¹⁰ is selected from the group consisting of C₃-C₁₀cycloalkylsubstituted with R¹⁹ and phenyl substituted with R²²;each R¹⁹ is independently selected from the group consisting of —CN,—C(═O)R⁴⁶, —CH(OH)—R⁴⁷, —(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—C≡C—R⁵¹R⁵²,—(CR⁴⁴R⁴⁵)_(m)—C≡C—R⁵³, —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀cycloalkyl substituted withR⁵⁵, and —(CR⁴⁴R⁴⁵)_(m)-aryl substituted with R⁵⁶ and R⁵⁷.each R²² is independently selected from the group consisting of halogen,—CN, hydroxy, —C(═O)OH, —C(═O)R⁴⁶, —CH(OH)—R⁴⁷, hydroxy,—(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)R⁴⁶,—(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—C≡C—R⁵¹R⁵², —(CR⁴⁴R⁴⁵)_(m)—C≡C—R⁵³,—(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀heterocyclyl substituted with R⁵⁴,—(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀cycloalkyl substituted with R⁵⁵,—(CR⁴⁴R⁴⁵)_(m)-aryl substituted with R⁵⁶ and R⁵⁷ and—(CR⁴⁴R⁴⁵)_(m)-heteroaryl substituted with R⁵⁶ and R⁵⁷;R²⁴ is selected from the group consisting of —C(═O)—R²⁶, —S(═O)₂—R²⁷,heteroaryl substituted with R²⁸, and aryl substituted with R²⁹;R²⁵ is selected from the group consisting of hydrogen, methyl, ethyl,isobutyl, isopropyl and cyclopropyl;R¹²⁵ is selected from the group consisting of hydrogen, methyl, ethyl,isobutyl, isopropyl and cyclopropyl;R³ is selected from the group consisting of C₃-C₁₀heterocyclylsubstituted with R³⁰ and R³¹, C₃-C₁₀cycloalkyl substituted with R⁹⁰ andR⁹¹, aryl substituted with R³⁰ and R³¹, heteroaryl substituted with R⁹⁰and R⁹¹, —C(═O)R³², —CH(OH)—R³³, —(CR⁴⁴R⁴⁵)_(n)—C(═O)—NR³⁴R³⁵,—(CR⁴⁴R⁴⁵)_(n)—NR³⁶C(═O)R³⁷, —(CR⁴⁴R⁴⁵)_(n)—OR³⁸, —(CR⁴⁴R⁴⁵)_(n)—SR³⁸,—(CR⁴⁴R⁴⁵)_(n)—S(═O)₂R³⁹, —(CR⁴⁴R⁴⁵)_(n)—S(═O)₂NR³⁴R³⁵,—(CR⁴⁴R⁴⁵)_(n)—NR³⁴S(═O)₂—R⁴⁰, —(CR⁴⁴R⁴⁵)_(n)—NR³⁴R³⁵,—(CR⁴⁴R⁴⁵)_(n)—NR³⁴C(═O)—NR³⁴R³⁵, —(CR⁴⁴R⁴⁵)_(n)—C≡C—R⁴¹R⁴², and—(CR⁴⁴R⁴⁵)_(n)—C≡C—R⁴³,n is selected from the group consisting of 0, 1 and 2;R⁴⁴ and R⁴⁵ are each independently selected from the group consistinghydrogen, halogen, C₁-C₆alkyl and C₃-C₁₀cycloalkyl, wherein saidC₁-C₆alkyl and C₃-C₁₀cycloalkyl are optionally substituted with one ortwo substituents selected independently from the group consistinghalogen, hydroxy and oxo; or R⁴⁴ and R⁴⁵ together with the carbon atomto which they are attached form a cyclopropyl or cyclobutyl ring,wherein said ring are optionally substituted with hydroxy or halogen;R⁷⁰ and R⁷¹ are each independently selected from the group consistinghydrogen, halogen, C₁-C₆alkyl and C₃-C₁₀cycloalkyl, wherein saidC₁-C₆alkyl and C₃-C₁₀cycloalkyl are optionally substituted with one ortwo substituents selected independently from the group consistinghalogen, hydroxy and oxo; or R⁴⁴ and R⁴⁵ together with the carbon atomto which they are attached form a cyclopropyl or cyclobutyl ring,wherein said ring are optionally substituted with hydroxy or halogen;R⁷² and R⁷³ are each independently selected from the group consistinghydrogen, halogen, C₁-C₆alkyl and C₃-C₁₀cycloalkyl, wherein saidC₁-C₆alkyl and C₃-C₁₀cycloalkyl are optionally substituted with one ortwo substituents selected independently from the group consistinghalogen, hydroxy and oxo; or R⁴⁴ and R⁴⁵ together with the carbon atomto which they are attached form a cyclopropyl or cyclobutyl ring,wherein said ring are optionally substituted with hydroxy or halogen;R³⁰, R³¹, R⁴² and R⁴³ are each independently selected from the groupconsisting of hydrogen, halogen, —CN, —C(═O)OH, —C(═O)R⁴⁶, —CH(OH)—R⁴⁷,trifluoromethyl, hydroxy, —(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)R⁴⁶, —(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹,—(CR⁴⁴—R⁴⁵)_(m)—S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—C≡CR⁵¹R⁵²,—(CR⁴⁴R⁴⁵)_(m)—C≡C—R⁵³, —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀heterocyclyl substitutedwith R⁵⁴, —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀cycloalkyl substituted with R⁵⁵,—(CR⁴⁴R⁴⁵)_(m)-aryl substituted with R⁵⁶ and R⁵⁷ and—(CR⁴⁴R⁴⁵)_(m)-heteroaryl substituted with R⁵⁶ and R⁵⁷;R⁹⁰ and R⁹¹ are each independently selected from the group consisting ofhydrogen, halogen, ═O, —CN, —C(═O)OH, —C(═O)R⁴⁶, —CH(OH)—R⁴⁷, hydroxy,trifluoromethyl, —(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)R⁴⁶, —(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—C≡CR⁵¹R⁵²,—(CR⁴⁴R⁴⁵)_(m)—C≡C—R⁵³, —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀heterocyclyl substitutedwith R⁵⁴, —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀cycloalkyl substituted with R⁵⁵,—(CR⁴⁴R⁴⁵)_(m)-aryl substituted with R⁵⁶ and R⁵⁷ and—(CR⁴⁴R⁴⁵)_(m)-heteroaryl substituted with R⁵⁶ and R⁵⁷;m is 0 or 1;R³², R³³, R³⁷, R³⁸, R³⁹, R⁴⁰ and R⁴¹ are each independently selectedfrom the group consisting of hydrogen, C₁-C₆alkyl, C₃-C₁₀heterocyclyl,C₃-C₁₀cycloalkyl, aryl and heteroaryl, wherein said C₁-C₆alkyl,C₃-C₁₀heterocyclyl, C₃-C₁₀cycloalkyl, aryl and heteroaryl are optionallysubstituted with one, two or three independently selected R⁵⁸;R³⁴, R³⁵, and R³⁶ are each independently selected from the groupconsisting of hydrogen, C₁-C₆alkyl, C₃-C₁₀cycloalkyl and heteroaryl,wherein said C₁-C₆alkyl, C₃-C₁₀cycloalkyl and heteroaryl are optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of halogen, methyl, ethyl and hydroxy; or R³⁴and R³⁵ together with the nitrogen to which they are attached form a 4to 6 membered ring, wherein said 4 to 6 membered ring optionally issubstituted with one or two substituents independently selected from thegroup consisting of hydroxy or halogen;R²⁶, R²⁷, R⁴⁶, R⁴⁷, R⁴⁹, R⁵⁰, R⁵¹, R⁵² and R⁵³ are each independentlyselected from the group consisting of hydrogen, C₁-C₆alkyl, heteroaryland C₃-C₁₀cycloalkyl, wherein said C₁-C₆alkyl, heteroaryl andC₃-C₁₀cycloalkyl are optionally substituted with one, two or threesubstituents independently selected from the group consisting ofhalogen, methyl, ethyl, methoxy, ethoxy, —OCH₂CH₂OH, carboxy andhydroxy;R⁵⁴, R⁵⁵, R⁵⁶ and R⁵⁷ are each independently selected from the groupconsisting of hydrogen, halogen, —CN, trifluoromethyl, —OCH₂CH₂OH,hydroxyl, C₁-C₆alkyl, heteroaryl and C₃-C₁₀cycloalkyl, wherein saidC₁-C₆alkyl, heteroaryl and C₃-C₁₀cycloalkyl are optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of halogen, methyl, ethyl, methoxy, ethoxy, —OCH₂CH₂OH,carboxy and hydroxy;R⁴⁸ and R⁴⁹ are each independently selected from the group consisting ofhydrogen, C₁-C₆alkyl, tetrahydropyrane, cyclohexyl and cyclopentyl,wherein said C₁-C₆alkyl, tetrahydropyrane, cyclohexyl and cyclopentylare optionally substituted with one or two substituents independentlyselected from the group consisting of halogen and hydroxy; or R⁴⁸ andR⁴⁹ together with the nitrogen to which they are attached form a 4 to 6membered ring, wherein said 4 to 6 membered ring optionally issubstituted with one or two substituents independently selected from thegroup consisting of hydroxy and halogen;R⁵⁸ are each independently selected from the group consisting ofhalogen, —CN, hydroxy, oxo, —C(═O)OH, —S(═O)₂R⁵⁹, —S—NR⁶⁰R⁶¹,S(═O)₂NR⁶⁰R⁶¹, cyclopropyl, —OR⁵⁹, C₁-C₆alkyl, —C(═O)NR⁶⁰R⁶¹,—NR⁶⁰C(═O)NR⁶¹R⁶⁰, —NR⁶⁰S(═O)₂R⁵⁹ and —NC(═O)R⁵⁹;R⁵⁹ is selected from the group consisting of hydrogen, C₁-C₆alkyl,C₃-C₁₀cycloalkyl, aryl and heteroaryl, wherein said C₁-C₆alkyl,C₃-C₁₀cycloalkyl, aryl and heteroaryl are optionally substituted withone, two or three substituents independently selected from the groupconsisting of halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl,—CN and hydroxy;R⁶⁰ and R⁶¹ are each independently selected from the group consisting ofhydrogen, C₁-C₆alkyl, C₃-C₁₀heterocyclyl, C₃-C₁₀cycloalkyl andheteroaryl, wherein said C₁-C₆alkyl, C₃-C₁₀heterocyclyl,C₃-C₁₀cycloalkyl and heteroaryl are optionally substituted with one ortwo substituents independently selected from the group consisting ofhalogen and hydroxy; or R⁶⁰ and R⁶¹ together with the nitrogen to whichthey are attached form a 4 to 6 membered ring, wherein said 4 to 6membered ring optionally is substituted with one or two substituentsindependently selected from the group consisting of hydroxy and halogen;R¹⁰³ is selected from the group consisting of C₃-C₁₀heterocyclylsubstituted with two substituents independently selected from the groupconsisting of R⁶² and R⁶³, C₃-C₁₀cycloalkyl substituted with R³⁰ andR³¹, aryl substituted with R³⁰ and R³¹, heteroaryl substituted with twosubstituents independently selected from the group consisting of R⁶² andR⁶³, —C(═O)R⁹³, —CH(OH)—R³³, —C(═O)—NR⁹⁴R⁹⁵, —NR³⁶C(═O)R³⁷, —OR³⁸,—SR³⁸, —S(═O)₂R³⁹, —S(═O)₂NR³⁴R³⁵, —NR³⁴S(═O)₂—R⁴⁰, —NR²⁴R²⁵—,—NR³⁴C(═O)—NR³⁴R³⁵, —C≡C substituted with R⁴¹ and R⁴², W and —C≡Csubstituted with R⁴³;W is selected from the group consisting of pyrrolidinone,tetrahydropyrane, 1,4-dioxane, aziridinone, azetidinone, piperidinone,thiazole, imidazole, tetrahydrofurane and oxepane;R⁹³ is selected from the group consisting of hydrogen,C₃-C₁₀heterocyclyl, C₃-C₁₀cycloalkyl, aryl and heteroaryl, wherein saidC₃-C₁₀heterocyclyl, C₃-C₁₀cycloalkyl, aryl and heteroaryl are optionallysubstituted with one, two or three independently selected R⁵⁸;R⁹⁴ and R⁹⁵ are each independently selected from the group consisting ofhydrogen, C₃-C₁₀cycloalkyl and heteroaryl, wherein said C₃-C₁₀cycloalkyland heteroaryl are optionally substituted with one, two or threesubstituents independently selected from the group consisting ofhalogen, methyl, ethyl and hydroxy; or R⁹⁴ and R⁹⁵ together with thenitrogen to which they are attached form a 4 to 6 membered ring, whereinsaid 4 to 6 membered ring optionally is substituted with one or twosubstituents independently selected from the group consisting of hydroxyor halogen;R⁶² is selected from the group consisting of halogen, C₁-C₆alkyl,—C(═O)OH, —CH(OH)—R⁴⁷, —C(═O)—NR⁴⁸R⁴⁹, —NR⁴⁸C(═O)R⁴⁶, —SR⁴⁹, —S(═O)₂R⁵⁰,—S(═O)₂NR⁴⁸R⁴⁰, —NR⁴⁸S(═O)₂R⁵⁰, —NR⁴⁸C(═O)—NR⁴⁸R⁴⁰, —C≡C—R⁵¹R⁵²,—C≡C—R⁵³, CH₂CH₂OH, —CH₂CH₂OH, C₃-C₁₀heterocyclyl substituted with R⁵⁴,C₃-C₁₀cycloalkyl substituted with R⁵⁵, aryl substituted with R⁵⁶ and R⁵⁷and heteroaryl substituted with R⁵⁶ and R⁵⁷;R⁶³ is selected from the group consisting of hydrogen, ═O, halogen,hydroxy, trifluoromethyl, —CN, oxo, —C(═O)OH, —S(═O)₂R⁵⁹,—S(═O)₂NR⁶⁰R⁶¹, —S(═O)NR⁶⁰R⁶¹ cyclopropyl, —OR⁵⁹, —SR⁵⁹, —C₁-C₆alkyl,—C(═O)NR⁶⁰R⁶¹, —NR⁶⁰C(═O)NR⁶¹R⁶⁰; —NR⁶⁰S(═O)₂R⁵⁹, and —N(C═O)R⁵⁹;a salt thereof with a pharmaceutically acceptable acid or base, or anyoptical isomer or mixture of optical isomers, including a racemicmixture, or any tautomeric forms.

The following aspects refer to compounds that fall within the scope ofFormula I:

In one aspect, Y is —X¹—X²—X³—R³.

In one aspect, X¹ is selected from the group consisting of —S— and—S(═O)₂—.

In one aspect, X¹ is —S(═O)₂.

In one aspect, X² is absent or is selected from the group consisting of—CR⁴⁴R⁴⁵— and —NR²⁵—.

In one aspect, X² is absent or is —CR⁴⁴R⁴⁵.

In one aspect, X³ is absent or is —CR⁷⁰R⁷¹—.

In one aspect, —X¹—X²—X³—R³ is selected from the group consisting of—S—R³, —S(═O)₂—R³, —S(═O)₂—NR²⁵R³, —S(═O)₂—CR⁴⁴R⁴⁵—R³.

In one aspect, —X¹—X²—X³—R³ is selected from the group consisting of—S—R³, —S(═O)₂—R³.

In one aspect, —X¹—X²—X³—R³ is selected from the group consisting of—S(═O)₂—NR²⁵R³, —S(═O)₂—CR⁴⁴R⁴⁵—R³.

In one aspect, Y is selected from the group consisting of—CR⁷²R⁷³—O—CR⁷⁰R⁷¹—R³, —CR⁷²R⁷³—S—CR⁷⁰R⁷¹—R³,—CR⁷²R⁷³—S(═O)₂—CR⁷⁰R⁷¹—R³, —CR⁷²R⁷³—NR²⁵—S(═O)₂—R³,—CR⁷²R⁷³—CR⁷⁰R⁷¹—S(═O)₂—R³, —CR⁷²R⁷³—CR⁷⁰R⁷¹—O—R³,—CR⁷²R⁷³—CR⁷⁰R⁷¹—S—R³, —CR⁷²R⁷³—CR⁷⁰R⁷¹—NR²⁵—R³, —O—CR⁴⁴R⁴⁵—S(═O)₂—R³,—CR⁷²R⁷³—O—R³, —CR⁷²R⁷³—S—R³, —CR⁷²R⁷³—S(═O)₂—R³, —CR⁷²R⁷³—NR²⁵—R³,—CR⁷²R⁷³—S(═O)₂—R³, —O—R¹⁰³, —O—CR⁴⁴R⁴⁵, —O—CR⁴⁴R⁴⁵—R¹⁰³,—CR⁷²R⁷³—CR⁴⁴R⁴⁵—R¹⁰³, —O—CR⁴⁴R⁴⁵—CR⁷⁰R⁷¹—R¹⁰³,—CR⁷²R⁷³—CR⁴⁴R⁴⁵—CR⁷⁰R⁷¹—R¹⁰³, and —CR⁷²R⁷³—R¹⁰³.

In one aspect, Y is selected from the group consisting of—CR⁷²R⁷³—O—CR⁷⁰R⁷¹—R³, —CR⁷²R⁷³—S—CR⁷⁰R⁷¹—R³,—CR⁷²R⁷³—S(═O)₂—CR⁷⁰R⁷¹—R³, —CR⁷²R⁷³—NR²⁵—S(═O)₂—R³,—CR⁷²R⁷³—CR⁷⁰R⁷¹—S(═O)₂—R³, —CR⁷²R⁷³—CR⁷⁰R⁷¹—O—R³ and—CR⁷²R⁷³—CR⁷⁰R⁷¹—NR²⁵—R³.

In one aspect, Y is selected from the group consisting of—CR⁷²R⁷³—O—CR⁷⁰R⁷¹—R³, —CR⁷²R⁷³—S—CR⁷⁰R⁷¹—R³, —CR⁷²R⁷³—CR⁷⁰R⁷¹—O—R³ and—CR⁷²R⁷³—CR⁷⁰R⁷¹—NR²⁵—R³.

In one aspect, Y is selected from the group consisting of—CR⁷²R⁷³—S(═O)₂—CR⁷⁰R⁷¹—R³, —CR⁷²R⁷³—CR⁷⁰R⁷¹—S(═O)₂—R³ and—CR⁷²R⁷³—NR²⁵—S(═O)₂—R³.

In one aspect, Y is selected from the group consisting of—CR⁷²R⁷³—O—CR⁷⁰R⁷¹—R³, —CR⁷²R⁷³—CR⁷⁰R⁷¹—O—R³ and—CR⁷²R⁷³—CR⁷⁰R⁷¹—NR²⁵—R³.

In one aspect, Y is selected from the group consisting ofC₃-C₁₀cycloalkyl substituted with R¹⁹ and phenyl substituted with R²².

In one aspect, Y is C₃-C₁₀cycloalkyl substituted with R¹⁹,

In one aspect, Y is phenyl substituted with R²².

In one aspect, R³ is selected from the group consisting ofC₃-C₁₀heterocyclyl substituted with R³⁰ and R³¹, C₃-C₁₀cycloalkylsubstituted with R⁹⁰ and R⁹¹, aryl substituted with R³⁰ and R³¹,heteroaryl substituted with R⁹⁰ and R⁹¹.

In one aspect, R³ is selected from the group consisting of —C(═O)R³²,—CH(OH)—R³³, —(CR⁴⁴—R⁴⁵)_(n)—C(═O)—NR³⁴R³⁵, —(CR⁴⁴R⁴⁵)_(n)—NR³⁶C(═O)R³⁷,—(CR⁴⁴R⁴⁵)_(n)—OR³⁸, —(CR⁴⁴R⁴⁵)_(n)—SR³⁸, —(CR⁴⁴—R⁴⁵)_(n)—S(═O)₂R³⁹,—(CR⁴⁴R⁴⁵)_(n)—S(═O)₂NR³⁴R³⁵, —(CR⁴⁴R⁴⁵)_(n)—NR³⁴S(═O)₂—R⁴⁰,—(CR⁴⁴R⁴⁵)_(n)—NR³⁴R³⁵, —(CR⁴⁴R⁴⁵)_(n)—NR³⁴C(═O)—NR³⁴R³⁵,—(CR⁴⁴R⁴⁵)_(n)—C═C—R⁴¹R⁴² and —(CR⁴⁴R⁴⁵)_(n)—C≡C—R⁴³.

In one aspect, R³ is selected from the group consisting ofC₃-C₁₀heterocyclyl substituted with R³⁰, C₃-C₁₀cycloalkyl substitutedwith R⁹⁰, aryl substituted with R³⁰, heteroaryl substituted with R⁹⁰,—(CR⁴⁴R⁴⁵)_(n)—C(═O)—NR³⁴R³⁵, —(CR⁴⁴R⁴⁵)_(n)—NR³⁶C(═O)R³⁷,—(CR⁴⁴R⁴⁵)_(n)—OR³⁸, —(CR⁴⁴—R⁴⁵)_(n)—S(═O)₂R³⁹,—(CR⁴⁴R⁴⁵)_(n)—S(═O)₂NR³⁴R³⁵, —(CR⁴⁴R⁴⁵)_(n)—NR³⁴S(═O)₂—R⁴⁰,—(CR⁴⁴R⁴⁵)_(n)—NR³⁴C(═O)—NR³⁴R³⁵, —(CR⁴⁴R⁴⁵)_(n)—C═CR⁴¹R⁴² and—(CR⁴⁴R⁴⁵)_(n)—C≡C—R⁴³.

In one aspect, R³ is selected from the group consisting ofC₃-C₁₀heterocyclyl substituted with R³⁰, C₃-C₁₀cycloalkyl substitutedwith R⁹⁰, aryl substituted with R³⁰; heteroaryl substituted with R⁹⁰,—C(═O)—NR³⁴R³⁵, —NR³⁶C(═O)R³⁷, —OR³⁸, —S(═O)₂R³⁹, —S(═O)₂NR³⁴R³⁵,—NR³⁴S(═O)₂—R⁴⁰, —NR³⁴C(═O)—NR³⁴R³⁵, —C═CR⁴¹R⁴² and —C≡C—R⁴³.

In one aspect, R³ is selected from the group consisting ofC₃-C₁₀heterocyclyl substituted with R³⁰, C₃-C₁₀cycloalkyl substitutedwith R⁹⁰, heteroaryl substituted with R³⁰, —C(═O)—NR³⁴R³⁵,—NR³⁶C(═O)R³⁷, —OR³⁸, —S(═O)₂R³⁹, —S(═O)₂NR³⁴R³⁵, —NR³⁴S(═O)₂—R⁴⁰,—NR³⁴C(═O)—NR³⁴R³⁵, —C═CR⁴¹R⁴² and —C≡C—R⁴³.

In one aspect, R³ is selected from the group consisting of piperidinesubstituted with R³⁰, pyrrolidine substituted with R³⁰, morpholinesubstituted with R³⁰, tetrahydropyranyl substituted with R³⁰, cyclohexylsubstituted with R³⁰, cyclopropyl substituted with R³⁰, cyclobutylsubstituted with R³⁰, cyclopentyl substituted with R³⁰, phenylsubstituted with R³⁰; pyridazinyl substituted with R³⁰, pyrazinylsubstituted with R³⁰, pyridine substituted with R³⁰, imidazolylsubstituted with R³⁰, pyrazolyl substituted with R³⁰ and pyrimidinylsubstituted with R³⁰, isoxazolyl substituted with R³⁰, pyridinylsubstituted with R³⁰, —C(═O)—NR³⁴R³⁵, —NR³⁶C(═O)R³⁷, —OR³⁸, —S(═O)₂R³⁹,—S(═O)₂NR³⁴R³⁵, —NR³⁴S(═O)₂—R⁴⁰, —NR³⁴C(═O)—NR³⁴R³⁵ and —C≡C—R⁴³.

In one aspect, R³ is selected from the group consisting of piperidinesubstituted with R³⁰, pyrrolidine substituted with R³⁰, morpholinesubstituted with R³⁰, tetrahydropyranyl substituted with R³⁰, cyclohexylsubstituted with R³⁰, cyclopropyl substituted with R³⁰, cyclobutylsubstituted with R³⁰, cyclopentyl substituted with R³⁰, phenylsubstituted with R³⁰; pyridazinyl substituted with R³⁰, pyrazinylsubstituted with R³⁰, pyridine substituted with R³⁰, imidazolylsubstituted with R³⁰, pyrazolyl substituted with R³⁰ and pyrimidinylsubstituted with R³⁰, isoxazolyl substituted with R³⁰, pyridinylsubstituted with R³⁰.

In one aspect, R³ is selected from the group consisting of—NR³⁶C(═O)R³⁷, —NR³⁴S(═O)₂—R⁴⁰ and —NR³⁴C(═O)—NR³⁴R³⁵.

In one aspect, R³ is selected from the group consisting of—C(═O)—NR³⁴R³⁵, —OR³⁸, —S(═O)₂R³⁹, —S(═O)₂NR³⁴R³⁵ and —C≡C—R⁴³.

In one aspect, n is selected from the group consisting of 0 or 1.

In one aspect, n is 0.

In one aspect, R¹⁰³ is selected from the group consisting of —C(═O)R⁹³,—CH(OH)—R³³, —C(═O)—NR⁹⁴R⁹⁵, —NR³⁶C(═O)R³⁷, —OR³⁸, —SR³⁸, —S(═O)₂R³⁹,—S(═O)₂NR³⁴R³⁵, —NR³⁴S(═O)₂—R⁴⁰, —NR²⁴R²⁵—, —NR³⁴C(═O)—NR³⁴R³⁵, —C═Csubstituted with R⁴¹ and R⁴², W and —C≡C substituted with R⁴³.

In one aspect, R¹⁰³ is selected from the group consisting ofC₃-C₁₀heterocyclyl substituted with two substitutions independentlyselected from the group consisting of R⁶² and R⁶³, C₃-C₁₀cycloalkylsubstituted with R³⁰ and R³¹, aryl substituted with R³⁰ and R³¹,heteroaryl substituted with two substitutions independently selectedfrom the group consisting of R⁶² and R⁶³.

In one aspect, R¹⁰³ is selected from the group consisting ofC₃-C₁₀heterocyclyl substituted with one or two substitutionsindependently selected from the group consisting of R⁶² and R⁶³ andheteroaryl substituted with two substitutions independently selectedfrom the group consisting of R⁶² and R⁶³.

In one aspect, R¹⁰³ is selected from the group consisting ofcyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl substituted with R³⁰and R³¹ and phenyl substituted with R³⁰ and R³¹, tetrahydropyranyl,piperidinyl, pyrrolidinyl and morpholinyl substituted with twosubstitutions independently selected from the group consisting of R⁶²and R⁶³ and imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinylpyrimidinyl and pyridinyl substituted with two substitutionsindependently selected from the group consisting of R⁶² and R⁶³.

In one aspect, R¹⁰³ is selected from the group consisting oftetrahydropyranyl, piperidinyl, pyrrolidinyl and morpholinyl substitutedwith two substitutions independently selected from the group consistingof R⁶² and R⁶³ and imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl,pyrazinyl pyrimidinyl and pyridinyl substituted with two substitutionsindependently selected from the group consisting of R⁶² and R⁶³.

In one aspect, R¹⁰³ comprises at least one R⁶² group.

In one aspect, R¹⁰³ is selected from the group consisting ofC₃-C₁₀cycloalkyl substituted with R³⁰ and R³¹ and aryl substituted withR³⁰ and R³¹;

In one aspect, R¹⁰³ is selected from the group consisting ofcyclopropyl, cyclobutyl, cyclohexyl, phenyl and cyclopentyl substitutedwith R³⁰ and R³¹;

In one aspect, R¹⁰³ is selected from the group consisting of—C(═O)—NR⁹⁴R⁹⁵, —NR³⁶C(═O)R³⁷, —OR³⁸, —SR³⁸, —S(═O)₂R³⁹, —S(═O)₂NR³⁴R³⁵,—NR³⁴S(═O)₂—R⁴⁰, —NR³⁴C(═O)—NR³⁴R³⁵, W and —C≡C substituted with R⁴³.

In one aspect, R¹⁰³ is selected from the group consisting of—C(═O)—NR⁹⁴R⁹⁵, —NR³⁶C(═O)R³⁷, —OR³⁸, —S(═O)₂R³⁹, —S(═O)₂NR³⁴R³⁵,—NR³⁴S(═O)₂—R⁴⁰, —NR³⁴C(═O)—NR³⁴R³⁵ and W.

In one aspect, R¹⁰³ is selected from the group consisting of—NR³⁶C(═O)R³⁷, —NR³⁴S(═O)₂—R⁴⁰ and —NR³⁴C(═O)—NR³⁴R³⁵.

In one aspect, R¹⁰³ is selected from the group consisting of—C(═O)—NR⁹⁴R⁹⁵, —OR³⁸, —S(═O)₂R³⁹, —S(═O)₂NR³⁴R³⁵ and W.

In one aspect, R¹⁰³ is W selected from the group consisting ofpyrrolidinone, tetrahydropyrane, 1,4-dioxane, piperidinone, thiazole,imidazole and tetrahydrofurane.

In one aspect, R¹⁰³ is W selected from the group consisting ofpyrrolidinone, tetrahydropyrane, piperidinone and imidazole.

In one aspect, R¹ is selected from the group consisting of hydrogen,methyl, ethyl, isopropyl and cyclopropyl and R² is selected from thegroup consisting of a monovalent radical having one of the followingformulae, wherein the symbol * denotes the point of attachment:

In one aspect, R¹ is selected from the group consisting of hydrogen andmethyl.

In one aspect, R¹ is hydrogen.

In one aspect, R¹ is methyl.

In one aspect, R² is selected from the group consisting of:

In one aspect, R² is selected from the group consisting of:

In one aspect, R² is

In one aspect, R² is

In one aspect, R² is

In one aspect, R² is

In one aspect, R² is

In one aspect, R² is

In one aspect, R¹ and R² together with the nitrogen to which they areattached is selected from the group consisting of:

In one aspect, R¹ and R² together with the nitrogen to which they areattached is

In one aspect, Q is a hydroxyl group.

In one aspect, Q is a carboxy group.

In one aspect, Q is a —S(═O)₂R⁶ group.

In one aspect, Q is selected is a —S(═O)₂NH₂ group.

In one aspect, P is a —S(═O)₂R⁶ group.

In one aspect, P is a carboxy group.

In one aspect, P is a —S(═O)₂NH₂ group.

In one aspect, R⁶ is selected from the group consisting of methyl,isopropyl, ethyl, phenyl, pyridine, cyclopropyl, cyclobutyl, cyclohexyland cyclopentyl, wherein said methyl, isopropyl, ethyl, phenyl,pyridine, cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl areoptionally substituted with one or two independently selected R⁷.

In one aspect, R⁶ is selected from the group consisting of methyl,ethyl, isopropyl, phenyl, pyridine, cyclopropyl and cyclohexyl, whereinsaid methyl, isopropyl, phenyl, pyridine, cyclopropyl and cyclohexyl areoptionally substituted with R⁷.

In one aspect, R⁷ is selected from the group consisting of hydrogen,methyl, cyclopropyl, —O—CH₃, —O-cyclopropyl, —O-isopropyl, hydroxy,fluoride and chloride, wherein said methyl, ethyl, cyclopropyl, —O—CH₃,—O-isopropyl and —O-cyclopropyl is optionally substituted with onesubstituent selected from the group consisting of hydroxy and halogen.

In one aspect, R⁷ is selected from the group consisting of hydrogen,methyl, cyclopropyl, —O-cyclopropyl, —O-isopropyl, hydroxy, fluoride andchloride, wherein said ethyl, cyclopropyl and —O-cyclopropyl isoptionally substituted with one substituent selected from the groupconsisting of hydroxy and halogen.

In one aspect, R⁴ is selected from the group consisting of hydrogen,methyl, isopropyl, ethyl, —O-methyl, —O-isopropyl, —O-ethyl, whereinsaid, methyl, isopropyl, ethyl, —O-methyl, —O-isopropyl, —O-ethyl aresubstituted with R¹² and R¹³, trifluoromethyl, CN, fluorine, chlorine,—S(═O)₂methyl, —S(═O)₂ethyl, —S(═O)₂cyclopropyl, —S(═O)₂NHR¹¹ and—C(═O)NHR¹⁰.

In one aspect, R⁴ is selected from the group consisting of hydrogen,methyl, isopropyl, ethyl, —O-methyl, —O-isopropyl, —O-ethyl, whereinsaid, methyl, isopropyl, ethyl, —O-methyl, —O-isopropyl, —O-ethyl are,substituted with R¹², trifluoromethyl, fluorine, chlorine,—S(═O)₂(methyl)₂, —S(═O)₂methyl, —S(═O)₂ethyl, —S(═O)₂cyclopropyl,—S(═O)₂Nmethyl, —S(═O)₂Nisopropyl, —C(═O)Nisopropyl, —C(═O)N(methyl)₂and —C(═O)Nmethyl.

In one aspect, R⁴ is selected from the group consisting of hydrogen,methyl, isopropyl, —O-methyl, —O-isopropyl, —O-ethyl, trifluoromethyl,fluorine, chlorine, —S(═O)₂methyl, —S(═O)₂ethyl, —S(═O)₂cyclopropyl,—S(═O)₂Nmethyl, —S(═O)₂Nisopropyl, —C(═O)Nisopropyl and —C(═O)Nmethyl.

In one aspect, R⁴ is in the ortho position.

In one aspect, R⁴ is in the meta position.

In one aspect, R⁹⁵ is selected from the group consisting of methyl,isopropyl, ethyl, phenyl, pyridine, pyrimidine, cyclopropyl, cyclobutyland cyclohexyl, wherein said ethyl, phenyl, pyridine, pyrimidine,cyclopropyl, cyclobutyl and cyclohexyl are optionally substituted withone or two independently selected R⁹⁶.

In one aspect, R⁹⁵ is selected from the group consisting of methyl,isopropyl, phenyl, pyridine, pyrimidine, cyclopropyl and cyclohexyl,wherein said ethyl, phenyl, pyridine, pyrimidine, cyclopropyl andcyclohexyl are optionally substituted with one R⁹⁶.

In one aspect, R⁹⁶ is selected from the group consisting of fluorine,chlorine, hydroxy, oxo, trifluoromethyl, methyl, isopropyl, ethyl and—S(═O)₂methyl.

In one aspect, R⁹⁶ is selected from the group consisting of fluorine,chlorine, hydroxy, trifluoromethyl, methyl, isopropyl and —S(═O)₂methyl.

In one aspect, R⁹⁷ is selected from the group consisting of hydrogen,methyl, isopropyl and ethyl.

In one aspect, R⁹⁷ is selected from the group consisting of hydrogen,methyl and isopropyl.

In one aspect, R¹² is selected from the group consisting of hydrogen,—O-(methyl, isopropyl, ethyl), fluorine, chlorine, carboxy and hydroxy.

In one aspect, R¹² is selected from the group consisting of hydrogen,—O-methyl, —O-isopropyl, fluorine and hydroxy.

In one aspect, R¹³ is selected from the group consisting of hydrogen,—O-(methyl, isopropyl, ethyl), fluorine, chlorine, carboxy and hydroxy.

In one aspect, R¹³ is selected from the group consisting of hydrogen,—O-methyl, —O-isopropyl, fluorine and hydroxy.

In one aspect, R⁵ is selected from the group consisting of hydrogen,methyl, isopropyl, ethyl, trifluoromethyl, CN, fluorine, chlorine,acetyl, ethyl, carbonyl, —S(═O)₂R¹⁷, S(═O)₂NR¹⁴R¹⁵, S-methyl,S-isopropyl, and S-ethyl; wherein said methyl, isopropyl, ethyl aresubstituted with R¹⁶ and; wherein said ethyl and carbonyl aresubstituted with R¹⁸.

In one aspect, R⁵ is selected from the group consisting of hydrogen,methyl, isopropyl, ethyl, trifluoromethyl, fluorine, chlorine, acetyl,—S(═O)₂methyl, —S(═O)₂ isopropyl, S(═O)₂NH₂, S(═O)₂N(CH₃)₂, S-methyl,S-isopropyl, and S-ethyl; wherein said methyl, isopropyl, and ethyl areoptionally substituted with fluorine or hydroxyl.

In one aspect, R⁵ is selected from the group consisting of hydrogen,methyl, isopropyl, trifluoromethyl, fluorine, chlorine, acetyl,—S(═O)₂methyl and —S(═O)₂ isopropyl.

In one aspect, R¹⁰ and R¹¹ are each independently selected from thegroup consisting of hydrogen, and C₁-C₄alkyl.

In one aspect, R¹⁰ and R¹¹ are each independently selected from thegroup consisting of hydrogen, methyl, ethyl and isopropyl.

In one aspect, R¹⁰ and R¹¹ together with the nitrogen to which they areattached form a piperidinyl, pyrrolidinyl and morpholinyl ring, whereinsaid ring optionally is substituted with one or two substituentsindependently selected from the group consisting of hydroxy andfluoride.

In one aspect, R¹⁰ and R¹¹ together with the nitrogen to which they areattached form a piperidinyl, ring, wherein said ring optionally issubstituted with one or two substituents independently selected from thegroup consisting of hydroxy and fluoride.

In one aspect, R¹⁴ and R¹⁵ are each independently selected from thegroup consisting of hydrogen, and C₁-C₄alkyl.

In one aspect, R¹⁴ and R¹⁵ are each independently selected from thegroup consisting of hydrogen, methyl, ethyl and isopropyl.

In one aspect, R¹⁴ and R¹⁵ together with the nitrogen to which they areattached form a piperidinyl, pyrrolidinyl and morpholinyl ring whereinsaid ring optionally is substituted with one or two substituentsindependently selected from the group consisting of hydroxy andfluoride.

In one aspect, R¹⁴ and R¹⁵ together with the nitrogen to which they areattached form a piperidinyl ring, wherein said ring optionally issubstituted with one or two substituents independently selected from thegroup consisting of hydroxy and fluoride

In one aspect, R¹⁶ is selected from the group consisting of hydrogen—O-methyl, methyl, cyclopropyl, fluorine, chlorine, —S(═O)₂-methyl,—S(═O)₂-ethyl, —C(═O)NH₂, —C(═O)N—CH₃CH₃, carboxy, and hydroxy.

In one aspect, R¹⁶ is selected from the group consisting of hydrogen,methyl, cyclopropyl, fluorine, —S(═O)₂-methyl, —C(═O)N—(CH₃)₂ andhydroxy.

In one aspect, R¹⁸ is selected from the group consisting of hydrogen—O-methyl, methyl, cyclopropyl, fluorine, chlorine, —S(═O)₂-methyl,—S(═O)₂-ethyl, —C(═O)NH₂, —C(═O)N—CH₃CH₃, carboxy, and hydroxy.

In one aspect, R¹⁸ is selected from the group consisting of hydrogen,methyl, cyclopropyl, fluoride, —S(═O)₂-methyl, —C(═O)N—(CH₃)₂ andhydroxy.

In one aspect, R¹⁷ is selected from the group consisting of hydrogen,methyl, ethyl and isopropyl, wherein said ethyl and isopropyl isoptionally substituted with one or two substituents selected from thegroup consisting of hydroxyl, fluorine and chlorine.

In one aspect, R¹⁷ is selected from the group consisting of hydrogen,methyl, ethyl and isopropyl, wherein said ethyl is optionallysubstituted with one substituents selected from the group consisting ofhydroxy and fluorine.

In one aspect, R¹⁹ is selected from the group consisting of halogen, —CN—C(═O)R⁴⁶, —CH(OH)—R⁴⁷, —(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—C═C—R⁵¹R⁵², and—(CR⁴⁴R⁴⁵)_(n)—C≡C—R⁵³.

In one aspect, R¹⁹ is selected from the group consisting of,—(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀cycloalkyl substituted with R⁵⁵, and—(CR⁴⁴R⁴⁵)_(m)-aryl substituted with R⁵⁶ and R⁵⁷.

In one aspect, R¹⁹ is selected from the group consisting of —CN,—(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹.

In one aspect, R¹⁹ is selected from the group consisting of,—C₃-C₁₀cycloalkyl substituted with R⁵⁵, and -phenyl substituted withR⁵⁶.

In one aspect, R¹⁹ is selected from the group consisting of —CN,—C(═O)—NR⁴⁸R⁴⁹, —NR⁴⁸C(═O)R⁴⁶, —OR⁴⁹, —S(═O)₂R⁵⁰, —S(═O)₂NR⁴⁸R⁴⁹,—NR⁴⁸S(═O)₂R⁵⁰, —NR⁴⁸C(═O)—NR⁴⁸R⁴⁹.

In one aspect, R²² is selected from the group consisting of halogen,—CN, hydroxy, —C(═O)OH, —C(═O)R⁴⁶, —CH(OH)—R⁴⁷, hydroxy,—(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)R⁴⁶,—(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹,—(CR⁴⁴—R⁴⁵)_(m)—C═C—R⁵¹R⁵², —(CR⁴⁴R⁴⁵)_(m)—C≡C—R⁵³.

In one aspect, R²² is selected from the group consisting of—(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀heterocyclyl substituted with R⁵⁴,—(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀cycloalkyl substituted with R⁵⁵,—(CR⁴⁴R⁴⁵)_(m)-aryl substituted with R⁵⁶ and R⁵⁷ and—(CR⁴⁴R⁴⁵)_(m)-heteroaryl substituted with R⁵⁶ and R⁵⁷.

In one aspect, R²² is selected from the group consisting of fluorine,chlorine, —CN, hydroxy, —C(═O)OH, —(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)R⁴⁶, —(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰, —(CR⁴⁴—R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹.

In one aspect, R²² is selected from the group consisting of—C₃-C₁₀heterocyclyl substituted with R⁵⁴, —C₃-C₁₀cycloalkyl substitutedwith R⁵⁵, -phenyl substituted with R⁵⁶ and -heteroaryl substituted withR⁵⁶.

In one aspect, R²² is selected from the group consisting of fluorine,chlorine, —CN, hydroxy, —C(═O)OH, —C(═O)—NR⁴⁸R⁴⁹, —NR⁴⁸C(═O)R⁴⁶, —OR⁴⁹,—S(═O)₂R⁵⁰, —S(═O)₂NR⁴⁸R⁴⁹, —NR⁴⁸S(═O)₂R⁸⁹, —NR⁴⁸C(═O)—NR⁴⁸R⁴⁹.

In one aspect, R²² is selected from the group consisting oftetrahydropyranyl, piperidinyl, pyrrolidinyl and morpholinyl substitutedwith R⁵⁴, cyclopropyl, cyclobutyl, cyclohexyl and cyclopentylsubstituted with R⁵⁵, -phenyl substituted with R⁵⁶ and imidazolyl,pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinylsubstituted with R⁵⁶.

In one aspect, R²² is selected from the group consisting oftetrahydropyranyl, piperidinyl and morpholinyl substituted with R⁵⁴,cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl substituted withR⁵⁵, -phenyl substituted with R⁵⁶ and pyridazinyl, pyrazinyl pyrimidinyland pyridinyl substituted with R⁸⁶.

In one aspect, R²² is selected from the group consisting of C═C—R⁵¹R⁵²,—C≡C—R⁵³ and —CH₂CH₂OH.

In one aspect, R²⁴ is selected from the group consisting of —C(═O)—R²⁶,—S(═O)₂—R²⁷, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinylpyrimidinyl and pyridinyl substituted with R²⁸, and phenyl substitutedwith R²⁹.

In one aspect, R²⁴ is selected from the group consisting of —C(═O)—R²⁶,—S(═O)₂—R²⁷, pyridazinyl, pyrazinyl pyrimidinyl and pyridinylsubstituted with R²⁸, and phenyl substituted with R²⁹.

In one aspect, R²⁵ is selected from the group consisting of hydrogen,methyl, ethyl, isopropyl and cyclopropyl.

In one aspect, R²⁵ is selected from the group consisting of hydrogen,methyl, isopropyl and cyclopropyl.

In one aspect, R¹²⁵ is selected from the group consisting of hydrogen,methyl, ethyl, isopropyl and cyclopropyl.

In one aspect, R¹²⁵ is selected from the group consisting of hydrogen,methyl, isopropyl and cyclopropyl.

In one aspect, R⁴⁴ and R⁴⁵ are each independently selected from thegroup consisting hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl,cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl, wherein said ethyl,isopropyl, cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl areoptionally substituted with one substituent selected independently fromthe group consisting of fluorine, chlorine, hydroxy and oxo.

In one aspect, R⁴⁴ and R⁴⁵ are each independently selected from thegroup consisting hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl,cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl, wherein said ethyl,cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl are optionallysubstituted with one substituent selected independently from the groupconsisting of fluorine and hydroxyl.

In one aspect, R⁴⁴ and R⁴⁵ together with the carbon atom to which theyare attached form a cyclopropyl ring, wherein said ring are optionallysubstituted with hydroxy or fluorine.

In one aspect, R⁴⁴ and R⁴⁵ together with the carbon atom to which theyare attached form a cyclobutyl ring, wherein said ring are optionallysubstituted with hydroxy or fluorine.

In one aspect, R⁷⁰ and R⁷¹ are each independently selected from thegroup consisting hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl,cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl, wherein said ethyl,isopropyl, cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl areoptionally substituted with one substituent selected independently fromthe group consisting of fluorine, chlorine, hydroxy and oxo.

In one aspect, R⁷⁰ and R⁷¹ are each independently selected from thegroup consisting hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl,cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl, wherein said ethyl,cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl are optionallysubstituted with one substituent selected independently from the groupconsisting of fluorine and hydroxyl.

In one aspect, R⁷⁰ and R⁷¹ together with the carbon atom to which theyare attached form a cyclopropyl ring, wherein said ring are optionallysubstituted with hydroxy or fluorine.

In one aspect, R⁷⁰ and R⁷¹ together with the carbon atom to which theyare attached form a cyclobutyl ring, wherein said ring are optionallysubstituted with hydroxy or fluorine.

In one aspect, R⁷² and R⁷³ are each independently selected from thegroup consisting hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl,cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl, wherein said ethyl,isopropyl, cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl areoptionally substituted with one substituent selected independently fromthe group consisting of fluorine, chlorine, hydroxy and oxo.

In one aspect, R⁷² and R⁷³ are each independently selected from thegroup consisting hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl,cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl, wherein said ethyl,cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl are optionallysubstituted with one substituent selected independently from the groupconsisting of fluorine and hydroxyl.

In one aspect, R⁷² and R⁷³ together with the carbon atom to which theyare attached form a cyclopropyl ring, wherein said ring are optionallysubstituted with hydroxy or fluorine.

In one aspect, R⁷² and R⁷³ together with the carbon atom to which theyare attached form a cyclobutyl ring, wherein said ring are optionallysubstituted with hydroxy or fluorine.

In one aspect, R³⁰ and R³¹ are each independently selected from thegroup consisting of hydrogen, halogen, CN, —C(═O)OH, —C(═O)R⁴⁶,—CH(OH)—R⁴⁷, hydroxy, —(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)R⁴⁶, —(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—C═C—R⁵¹R⁵², and—(CR⁴⁴R⁴⁵)_(m)—C≡C—R⁵³.

In one aspect, R³⁰ and R³¹ are each independently selected from thegroup consisting of hydrogen, halogen, CN, —C(═O)OH, hydroxy,—(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)R⁴⁶,—(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, and —(CR⁴⁴R⁴⁵)_(m)—C≡C—R⁵³.

In one aspect, R³⁰ ad R³¹ are each independently selected from the groupconsisting of hydrogen, halogen, CN, —C(═O)OH, hydroxy, —C(═O)—NR⁴⁸R⁴⁹,—NR⁴⁸C(═O)R⁴⁶, —OR⁴⁹, —S(═O)₂R⁵⁰, —S(═O)₂NR⁴⁸R⁴⁹, —NR⁴⁸S(═O)₂R⁵⁰,—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹ and —C≡C—R⁵³.

In one aspect, R³⁰ ad R³¹ are each independently selected from the groupconsisting of hydrogen, halogen, CN, —C(═O)OH, hydroxy, —C(═O)—NR⁴⁸R⁴⁹,—S(═O)₂R⁵⁰ and —S(═O)₂NR⁴⁸R⁴⁹.

In one aspect, R³⁰ ad R³¹ are each independently selected from the groupconsisting of hydrogen, halogen, CN, —C(═O)OH, hydroxy, —NR⁴⁸C(═O)R⁴⁶,—OR⁴⁹, —NR⁴⁸S(═O)₂R⁵⁰ and —NR⁴⁸C(═O)—NR⁴⁸R⁴⁹.

In one aspect, R³⁰ ad R³¹ are each independently selected from the groupconsisting of hydrogen, chlorine, fluorine, CN, —C(═O)OH, hydroxy,—NHC(═O)C₁₋₄alkyl, —OC₁₋₄alkyl, —OCH₂CH₂OH, —NHS(═O)₂C₁₋₄alkyl and—NHC(═O)—N(C₁₋₄alkyl)₂.

In one aspect, R³⁰, R³¹, R⁴² and R⁴³ are each independently selectedfrom the group consisting of —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀heterocyclylsubstituted with R⁵⁴, —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀-cycloalkyl substituted withR⁵⁵, —(CR⁴⁴R⁴⁵)_(m)-aryl substituted with R⁵⁶ and R⁵⁷ and—(CR⁴⁴R⁴⁵)_(m)-heteroaryl substituted with R⁵⁶ and R⁵⁷.

In one aspect, R³⁰, R³¹, R⁴² and R⁴³ are each independently selectedfrom the group consisting of —C₃-C₁₀heterocyclyl substituted with R⁵⁴,—C₃-C₁₀cycloalkyl substituted with R⁵⁵, -phenyl substituted with R⁵⁶ andR⁵⁷ and -heteroaryl substituted with R⁵⁶ and R⁵⁷.

In one aspect, R³⁰, R³¹, R⁴² and R⁴³ are each independently selectedfrom the group consisting of tetrahydropyranyl, piperidinyl,pyrrolidinyl and morpholinyl substituted with R⁵⁴, cyclopropyl,cyclobutyl, cyclohexyl and cyclopentyl substituted with R⁵⁵, phenylsubstituted with R⁵⁶ and R⁵⁷ and imidazolyl, pyrazolyl, isoxazolyl,pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl substituted with R⁵⁶and R⁵⁷.

In one aspect, R³⁰, R³¹, R⁴² and R⁴³ are each independently selectedfrom the group consisting of tetrahydropyranyl, piperidinyl,pyrrolidinyl and morpholinyl substituted with R⁵⁴, cyclopropyl,cyclobutyl and cyclohexyl substituted with R⁵⁵, phenyl substituted withR⁵⁶ and R⁵⁷ and pyridazinyl, pyrazinyl pyrimidinyl and pyridinylsubstituted with R⁵⁶ and R⁵⁷.

In one aspect, R⁹⁰ and R⁹¹ are each independently selected from thegroup consisting of hydrogen, halogen, ═O, —CN, —C(═O)OH, —C(═O)R⁴⁶,—CH(OH)—R⁴⁷, hydroxy, trifluoromethyl, —(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)R⁴⁶, —(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁶, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—C═CR⁵¹R⁵², and—(CR⁴⁴R⁴⁵)_(n)—C≡C—R⁵³.

In one aspect, R⁹⁰ and R⁹¹ are each independently selected from thegroup consisting of hydrogen, fluorine, chlorine, ═O, —CN, —C(═O)OH,hydroxy, —(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)R⁴⁶,—(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—C═CR⁵¹R⁵², and—(CR⁴⁴R⁴⁵)_(n)—C≡C—R⁵³.

In one aspect, R⁹⁰ and R⁹¹ are each independently selected from thegroup consisting of hydrogen, fluorine, chlorine, —CN, —C(═O)OH,—NR⁴⁸C(═O)R⁴⁶, —NR⁴⁸S(═O)₂R⁵⁰, and —NR⁴⁸C(═O)—NR⁴⁸R⁴⁹.

In one aspect, R⁹⁰ and R⁹¹ are each independently selected from thegroup consisting of hydrogen, fluorine, chlorine, ═O, —CN, —C(═O)OH,—C(═O)—NR⁴⁸R⁴⁹, —OR⁴⁹, —SR⁴⁹, —S(═O)₂R⁵⁰, —S(═O)₂NR⁴⁸R⁴⁹, —C═CR⁵¹R⁵² and—C≡C—R⁵³.

In one aspect, R⁹⁰ and R⁹¹ are each independently selected from thegroup consisting of hydrogen, —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀heterocyclylsubstituted with R⁵⁴, —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀cycloalkyl substituted withR⁵⁵, —(CR⁴⁴R⁴⁵)_(m)-aryl substituted with R⁵⁶ and R⁵⁷ and—(CR⁴⁴R⁴⁵)_(m)-heteroaryl substituted with R⁵⁶ and R⁵⁷.

In one aspect, R⁹⁰ and R⁹¹ are each independently selected from thegroup consisting of hydrogen, tetrahydropyranyl, piperidinyl,pyrrolidinyl and morpholinyl substituted with R⁵⁴, cyclopropyl,cyclobutyl, cyclohexyl and cyclopentyl substituted with R⁵⁵, phenylsubstituted with R⁵⁶ and R⁵⁷ and -imidazolyl, pyrazolyl, isoxazolyl,pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl substituted with R⁵⁶and R⁵⁷.

In one aspect, R⁹⁰ and R⁹¹ are each independently selected from thegroup consisting of hydrogen, tetrahydropyranyl, piperidinyl andmorpholinyl substituted with R⁵⁴, cyclopropyl, cyclobutyl and cyclohexylsubstituted with R⁵⁵, phenyl substituted with R⁵⁶ and R⁵⁷ andpyridazinyl, pyrazinyl pyrimidinyl and pyridinyl substituted with R⁵⁶and R⁵⁷.

In one aspect, m is 0.

In one aspect, m is 1.

In one aspect, R³², R³³, R³⁷, R³⁸, R³⁹, R⁴⁰ and R⁴¹ are eachindependently selected from the group consisting of hydrogen, C₁-C₆alkyland C₃-C₁₀cycloalkyl, wherein said C₁-C₆alkyl and C₃-C₁₀cycloalkyl areoptionally substituted with one or two independently selected R⁵⁸.

In one aspect, R³², R³³, R³⁷, R³⁸, R³⁹, R⁴⁰ and R⁴¹ are eachindependently selected from the group consisting of hydrogen, C₁-C₆alkyland C₃-C₁₀cycloalkyl, wherein said C₁-C₆alkyl and C₃-C₁₀cycloalkyl areoptionally substituted with one R⁵⁸.

In one aspect, R³², R³³, R³⁷, R³⁸, R³⁹, R⁴⁰ and R⁴¹ are eachindependently selected from the group consisting of hydrogen, methyl,ethyl and isopropyl, trifluoromethyl and cyclopropyl, cyclobutyl,cyclohexyl and cyclopentyl, wherein said methyl, ethyl and isopropyl,trifluoromethyl and cyclopropyl, cyclobutyl, cyclohexyl and cyclopentylare optionally substituted with one R⁵⁸.

In one aspect, R³², R³³, R³⁷, R³⁸, R³⁹, R⁴⁰ and R⁴¹ are eachindependently selected from the group consisting of hydrogen,C₃-C₁₀heterocyclyl, aryl and heteroaryl, wherein saidC₃-C₁₀heterocyclyl, aryl and heteroaryl are optionally substituted withone or two independently selected R⁵⁸.

In one aspect, R³², R³³, R³⁷, R³⁸, R³⁹, R⁴⁰ and R⁴¹ are eachindependently selected from the group consisting of hydrogen,C₃-C₁₀heterocyclyl, aryl and heteroaryl, wherein saidC₃-C₁₀heterocyclyl, aryl and heteroaryl are optionally substituted withone or two independently selected R⁵⁸.

In one aspect, R³², R³³, R³⁷, R³⁸, R³⁹, R⁴⁰ and R⁴¹ are eachindependently selected from the group consisting of hydrogen,tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl,imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyland pyridinyl wherein said tetrahydropyranyl, piperidinyl, pyrrolidinyl,morpholinyl, phenyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl,pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with oneor two independently selected R⁵⁸.

In one aspect, R³², R³³, R³⁷, R³⁸, R³⁹, R⁴⁰ and R⁴¹ are eachindependently selected from the group consisting of hydrogen,tetrahydropyranyl, piperidinyl, morpholinyl, phenyl, pyridazinyl,pyrazinyl, pyrimidinyl and pyridinyl wherein said tetrahydropyranyl,piperidinyl, morpholinyl, phenyl, pyridazinyl, pyrazinyl, pyrimidinyland pyridinyl are optionally substituted with one R⁵⁸.

In one aspect, R³⁴, R³⁵, and R³⁶ are each independently selected fromthe group consisting of hydrogen, C₁-C₆alkyl, C₃-C₁₀cycloalkyl andheteroaryl, wherein said C₁-C₆alkyl, C₃-C₁₀-cycloalkyl and heteroarylare optionally substituted with one, two or three substituentsindependently selected from the group consisting of halogen, methyl,ethyl and hydroxyl.

In one aspect, R³⁴ and R³⁵ together with the nitrogen to which they areattached form a piperidinyl, pyrrolidinyl and morpholinyl ring, whereinsaid ring optionally is substituted with one or two substituentsindependently selected from the group consisting of hydroxy or fluorine.

In one aspect, R³⁴, R³⁵, and R³⁶ are each independently selected fromthe group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl,cyclobutyl, cyclohexyl, cyclopentyl, imidazolyl, pyrazolyl, isoxazolyl,pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl, wherein said methyl,ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyland pyridinyl are optionally substituted with one, two or threesubstituents independently selected from the group consisting offluorine, methyl, ethyl and hydroxyl.

In one aspect, R³⁴, R³⁵, and R³⁶ are each independently selected fromthe group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl,cyclobutyl, cyclohexyl, cyclopentyl, imidazolyl, pyrazolyl, isoxazolyl,pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl, wherein said methyl,ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyland pyridinyl are optionally substituted with one substituentindependently selected from the group consisting of fluorine, methyl,ethyl and hydroxyl.

In one aspect, R²⁶, R²⁷, R⁴⁶, R⁴⁷, R⁴⁹, R⁵⁰, R⁵¹, R⁵³ and R⁵² are eachindependently selected from the group consisting of hydrogen,C₁-C₆alkyl, heteroaryl and C₃-C₁₀cycloalkyl, wherein said C₁-C₆alkyl,heteroaryl and C₃-C₁₀cycloalkyl are optionally substituted with one, twoor three substituents independently selected from the group consistingof halogen, methyl, ethyl, methoxy, ethoxy, —OCH₂CH₂OH, carboxy andhydroxy.

In one aspect, R⁵⁴, R⁵⁵, R⁵⁶ and R⁵⁷ are each independently selectedfrom the group consisting of hydrogen, C₁-C₆alkyl, heteroaryl andC₃-C₁₀cycloalkyl, wherein said C₁-C₆alkyl, heteroaryl andC₃-C₁₀cycloalkyl are optionally substituted with one, two or threesubstituents independently selected from the group consisting ofhalogen, methyl, ethyl, methoxy, ethoxy, —OCH₂CH₂OH, carboxy andhydroxy.

In one aspect, R²⁶, R²⁷, R⁴⁶, R⁴⁷, R⁴⁹, R⁵⁰, R⁵¹, R⁵³ and R⁵² are eachindependently selected from the group consisting of hydrogen, methyl,ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyland pyridinyl, wherein said methyl, ethyl, isopropyl, cyclopropyl,cyclobutyl, cyclohexyl, cyclopentyl, imidazolyl, pyrazolyl, isoxazolyl,pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl are optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of fluorine, chlorine, methyl, ethyl, methoxy,ethoxy, —OCH₂CH₂OH, carboxy and hydroxy.

In one aspect, R⁵⁴, R⁵⁵, R⁵⁶ and R⁵⁷ are each independently selectedfrom the group consisting of hydrogen, halogen, —CN, trifluoromethyl,—OCH₂CH₂OH, hydroxyl.

In one aspect, R⁵⁴, R⁵⁵, R⁵⁶ and R⁵⁷ are each independently selectedfrom the group consisting of hydrogen, methyl, ethyl, isopropyl,cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, imidazolyl, pyrazolyl,isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl, whereinsaid methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl,cyclopentyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl,pyrimidinyl and pyridinyl are optionally substituted with one, two orthree substituents independently selected from the group consisting offluorine, chlorine methyl, ethyl, methoxy, ethoxy, —OCH₂CH₂OH, carboxyand hydroxy.

In one aspect, R⁴⁸ is selected from the group consisting of hydrogen,methyl, ethyl and isopropyl, tetrahydropyrane, cyclohexyl andcyclopentyl wherein said methyl, ethyl and isopropyl, tetrahydropyrane,cyclohexyl and cyclopentyl are optionally substituted with one or twosubstituents independently selected from the group consisting offluorine and hydroxy.

In one aspect, R⁴⁹ is selected from the group consisting of hydrogen,methyl, ethyl and isopropyl, tetrahydropyrane, cyclohexyl andcyclopentyl wherein said methyl, ethyl and isopropyl, tetrahydropyrane,cyclohexyl and cyclopentyl are optionally substituted with one or twosubstituents independently selected from the group consisting offluorine and hydroxy.

In one aspect, R⁴⁹ is H and R⁴⁸ is selected from the group consisting ofhydrogen, methyl, ethyl and isopropyl, tetrahydropyrane, cyclohexyl andcyclopentyl wherein said methyl, ethyl and isopropyl, tetrahydropyrane,cyclohexyl and cyclopentyl are optionally substituted with one or twosubstituents independently selected from the group consisting offluorine and hydroxy.

In one aspect, R⁴⁸ is H and R⁴⁹ is selected from the group consisting ofhydrogen, methyl, ethyl and isopropyl, tetrahydropyrane, cyclohexyl andcyclopentyl wherein said methyl, ethyl and isopropyl, tetrahydropyrane,cyclohexyl and cyclopentyl are optionally substituted with one or twosubstituents independently selected from the group consisting offluorine and hydroxy.

In one aspect, R⁴⁸ and R⁴⁹ together with the nitrogen to which they areattached form a piperidinyl, pyrrolidinyl and morpholinyl ring, whereinsaid ring optionally is substituted with one or two substituentsindependently selected from the group consisting of hydroxy andfluoride.

In one aspect, R⁵⁸ are each independently selected from selected fromthe group consisting of halogen, —CN, hydroxy, oxo, —C(═O)OH,—S(═O)₂R⁵⁹, —S—NR⁶⁰R⁶¹, S(═O)₂NR⁶⁰R⁶¹, cyclopropyl, —OR⁵⁹, —SR⁵⁹,C₁-C₆alkyl, —C(═O)NR⁶⁰R⁶¹, —NR⁶⁰C(═O)NR⁶¹R⁶⁰, —NR⁶⁰S(═O)₂R⁵⁹ and—NC(═O)R⁵⁹.

In one aspect, R⁵⁸ is selected from the group consisting of fluorine,chlorine, —CN, hydroxy, oxo, —C(═O)OH, —S(═O)₂R⁵⁹, —S(═O)₂NR⁶⁰R⁶¹,cyclopropyl, —OR⁵⁹, —SR⁵⁹, methyl, ethyl, isopropyl, —C(═O)NR⁶⁰R⁶¹,—NR⁶⁰C(═O)NR⁶¹R⁶⁰, —NR⁶⁰S(═O)₂R⁵⁹ and —NC(═O)R⁵⁹.

In one aspect, R⁵⁸ are each independently selected from selected fromthe group consisting of fluorine, chlorine, —CN, hydroxy, oxo, —C(═O)OH,—S(═O)₂R⁵⁹, cyclopropyl, —OR⁵⁹, methyl, ethyl, isopropyl and—C(═O)NR⁶⁰R⁶¹.

In one aspect, R⁵⁸ are each independently selected from selected fromthe group consisting of —S(═O)₂NR⁶⁰R⁶¹, —SR⁵⁹, —NR⁶⁰C(═O)NR⁶¹R⁶⁰,—NR⁶⁰S(═O)₂R⁵⁹ and —NC(═O)R⁵⁹.

In one aspect, R⁵⁹ is selected from the group consisting of hydrogen,C₁-C₆alkyl and C₃-C₁₀cycloalkyl wherein said —C₆alkyl, C₃-C₁₀cycloalkylare optionally substituted with one, two or three substituentsindependently selected from the group consisting of halogen, methyl,ethyl, methoxy, ethoxy trifluoromethyl and hydroxy.

In one aspect, R⁵⁹ is selected from the group consisting of hydrogen,phenyl and heteroaryl, wherein said, phenyl and heteroaryl areoptionally substituted with one, two or three substituents independentlyselected from the group consisting of halogen, methyl, ethyl, methoxy,ethoxy and hydroxy.

In one aspect, R⁵⁹ is selected from the group consisting of hydrogen,methyl, ethyl and isopropyl, cyclopropyl, cyclobutyl, cyclohexyl,cyclopentyl, phenyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl,pyrazinyl, pyrimidinyl and pyridinyl, wherein said methyl, ethyl andisopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl,imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyland pyridinyl are optionally substituted with one, two or threesubstituents independently selected from the group consisting ofhalogen, methyl, ethyl, methoxy, ethoxy and hydroxy.

In one aspect, R⁶⁰ are each independently selected from the groupconsisting of hydrogen, methyl, ethyl, isopropyl, tetrahydropyranyl,piperidinyl, pyrrolidinyl, morpholinyl, cyclopropyl, cyclobutyl,cyclohexyl, cyclopentyl, and heteroaryl, wherein said methyl, ethyl,isopropyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl,cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and heteroaryl areoptionally substituted with one or two substituents independentlyselected from the group consisting of fluorine, chlorine and hydroxy.

In one aspect, R⁶⁰ are each independently selected from the groupconsisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, whereinsaid methyl, ethyl, isopropyl and cyclopropyl are optionally substitutedwith one or two substituents independently selected from the groupconsisting of fluorine, chlorine and hydroxy.

In one aspect, R⁶¹ are each independently selected from the groupconsisting of hydrogen, C₁-C₆alkyl, C₃-C₁₀heterocyclyl, C₃-C₁₀cycloalkyland heteroaryl, wherein said C₁-C₆alkyl, C₃-C₁₀heterocyclyl,C₃-C₁₀cycloalkyl and heteroaryl are optionally substituted with one ortwo substituents independently selected from the group consisting ofhalogen and hydroxy.

In one aspect, R⁶¹ are each independently selected from the groupconsisting of hydrogen, methyl, ethyl, isopropyl, tetrahydropyranyl,piperidinyl, pyrrolidinyl, morpholinyl, cyclopropyl, cyclobutyl,cyclohexyl, cyclopentyl, and heteroaryl, wherein said methyl, ethyl,isopropyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl,cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and heteroaryl areoptionally substituted with one or two substituents independentlyselected from the group consisting of fluorine, chlorine and hydroxy.

In one aspect, R⁹³ is selected from the group consisting of hydrogen,methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl,cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl,phenyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl,pyrimidinyl and pyridinyl, wherein said methyl, ethyl, isopropyl,cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl,piperidinyl, pyrrolidinyl, morpholinyl, phenyl, imidazolyl, pyrazolyl,isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl areoptionally substituted with one, two or three independently selectedR⁵⁸.

In one aspect, R⁹³ is selected from the group consisting of hydrogen,methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl,cyclopentyl, tetrahydropyranyl, piperidinyl, morpholinyl, phenyl,pyrimidinyl and pyridinyl, wherein said methyl, ethyl, isopropyl,cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl,piperidinyl, morpholinyl, phenyl, pyrimidinyl and pyridinyl areoptionally substituted with one, two or three independently selectedR⁵⁸.

In one aspect, R⁹⁴ and R⁹⁵ are each independently selected from thegroup consisting of hydrogen, cyclopropyl, cyclobutyl, cyclohexyl,cyclopentyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl,pyrimidinyl and pyridinyl, wherein said cyclopropyl, cyclobutyl,cyclohexyl, cyclopentyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl,pyrazinyl, pyrimidinyl and pyridinyl are optionally substituted withone, two or three substituents independently selected from the groupconsisting of fluorine, chlorine, methyl, ethyl and hydroxy.

In one aspect, R⁹⁴ is hydrogen and R⁹⁵ are selected from the groupconsisting of hydrogen, cyclopropyl, cyclobutyl, cyclohexyl,cyclopentyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl,pyrimidinyl and pyridinyl, wherein said cyclopropyl, cyclobutyl,cyclohexyl, cyclopentyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl,pyrazinyl, pyrimidinyl and pyridinyl are optionally substituted withone, two or three substituents independently selected from the groupconsisting of fluorine, chlorine, methyl, ethyl and hydroxy.

In one aspect, R⁹⁴ and R⁹⁵ together with the nitrogen to which they areattached form a piperidinyl, pyrrolidinyl and morpholinyl ring, whereinsaid ring optionally is substituted with one or two substituentsindependently selected from the group consisting of hydroxy or fluorine.

In one aspect, R⁹⁴ and R⁹⁵ together with the nitrogen to which they areattached form a piperidinyl and pyrrolidinyl ring, wherein said ringoptionally is substituted with one or two substituents independentlyselected from the group consisting of hydroxy or fluorine.

In one aspect, R⁶² is selected from the group consisting of fluoride,chloride, methyl, —C(═O)OH, —CH(OH)—R⁴⁷, —C(═O)—NR⁴⁸R⁴⁹, —NR⁴⁵C(═O)R⁴⁶,—SR⁴⁹, —S(═O)₂R⁵⁰, —S(═O)₂NR⁴⁸R⁴⁹, —NR⁴⁸S(═O)₂R⁵⁰, —NR⁴⁵C(═O)—NR⁴⁸R⁴⁹,—C═C—R⁵¹R⁵², —C≡C—R⁵³, and CH₂CH₂OH, —CH₂CH₂OH.

In one aspect, R⁶² is selected from the group consisting ofC₃-C₁₀heterocyclyl substituted with R⁵⁴, C₃-C₁₀cycloalkyl substitutedwith R⁵⁵, aryl substituted with R⁵⁶ and R⁵⁷ and heteroaryl substitutedwith R⁵⁶ and R⁵⁷.

In one aspect, R⁶² is selected from the group consisting of fluorine,chlorine, methyl, —CH(OH)-cyclopropyl, —C(═O)—NR⁴⁸R⁴⁹, —NR⁴⁸C(═O)R⁴⁶,—S(═O)₂R⁵⁰, —S(═O)₂NR⁴⁸R⁴⁹, —NR⁴⁸S(═O)₂R⁵⁰, —NR⁴⁸C(═O)—NR⁴⁸R⁴⁹,CH₂CH₂OH, —CH₂CH₂OH.

In one aspect, R⁶² is selected from the group consisting oftetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl substitutedwith R⁵⁴, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl substitutedwith R⁵⁵, phenyl substituted with R⁵⁶ and R⁵⁷ and imidazolyl, pyrazolyl,isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinylsubstituted with R⁵⁶ and R⁵⁷.

In one aspect, R⁶³ is selected from the group consisting of hydrogen,fluoride, chloride, hydroxy, oxo, —S(═O)₂R⁵⁹, —S(═O)₂NR⁶⁰R⁶¹,—S(═O)NR⁶⁰R⁶¹ cyclopropyl, —OR⁵⁹, methyl, ethyl, isopropyl,—C(═O)NR⁶⁰R⁶¹, —NR⁶⁰C(═O)NR⁶¹R⁶⁰; —NR⁶⁰S(═O)₂R⁵⁹, and —N(C═O)R⁵⁹.

In one aspect, R⁶³ is selected from the group consisting of hydrogen,fluoride, chloride, hydroxy, oxo, —S(═O)₂R⁵⁹, —S(═O)₂NR⁶⁰R⁶¹,—S(═O)NR⁶⁰R⁶¹ cyclopropyl, —OR⁵⁹, methyl, ethyl, isopropyl and—C(═O)NR⁶⁰R⁶¹.

In one aspect, R⁶³ is selected from the group consisting of hydrogen,fluoride, chloride, trifluoromethyl, hydroxy, oxo, —S(═O)₂cyclopropyl,—S(═O)₂methyl, cyclopropyl, —OR⁵⁹, methyl, ethyl and isopropyl.

In one aspect, the compound of the invention is selected from the groupconsisting ofN-(5-Hydroxy-adamantan-2-yl)-N-methyl-3-phenethyloxy-benzamide,N-(5-Hydroxy-adamantan-2-yl)-3-phenethyloxy-benzamide,3-Cyclohexylmethoxy-N-(5-hydroxy-adamantan-2-yl)-N-methyl-benzamide,N-(5-Hydroxy-adamantan-2-yl)-N-methyl-3-(1-methyl-butoxy)-benzamide,N-(5-Hydroxy-adamantan-2-yl)-3-methoxy-N-methyl-benzamide,N-(5-Hydroxy-adamantan-2-yl)-N-methyl-3-(2-pyridin-2-yl-ethoxy)-benzamide,N-(5-Hydroxy-adamantan-2-yl)-3-(2-pyridin-2-yl-ethoxy)-benzamide,3-Benzyloxy-N-(5-hydroxy-adamantan-2-yl)-benzamide,N-(5-Hydroxy-adamantan-2-yl)-3-(2-morpholin-4-yl-ethoxy)-benzamide,4-{2-[3-(5-Hydroxy-adamantan-2-ylcarbamoyl)-phenoxy]-ethyl}-piperidine-1-carboxylicacid isopropylamide,3-[2-(1-Cyclopropanesulfonyl-piperidin-4-yl)-ethoxy]-N-(5-hydroxy-adamantan-2-yl)-benzamide,3-(6-Chloro-pyridin-3-ylmethoxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide,N-(5-Hydroxy-adamantan-2-yl)-3-(tetrahydro-pyran-4-ylmethoxy)-benzamide,N-(5-Hydroxy-adamantan-2-yl)-3-[2-(tetrahydro-pyran-4-yl)-ethoxy]-benzamide,N-(5-Hydroxy-adamantan-2-yl)-3-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-benzamide,N-(5-Hydroxy-adamantan-2-yl)-N-methyl-3-(tetrahydro-pyran-4-yloxy)-benzamide′,(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-[3-(tetrahydro-pyran-4-ylmethoxy)-phenyl]-methanone,(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-{3-[2-(tetrahydro-pyran-4-yl)-ethoxy]-phenyl}-methanone,(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-[3-(4-hydroxy-cyclohexylmethoxy)-phenyl]-methanone.

In one embodiment the compound of the invention is an agent useful forthe treatment, prevention and/or prophylaxis of any conditions,disorders and diseases wherein a modulation or an inhibition of theactivity of 11βHSD1 is beneficial.

In one embodiment the compound of the invention is an agent useful forthe treatment, prevention and/or prophylaxis of any conditions,disorders and diseases that are influenced by intracellularglucocorticoid levels.

In one embodiment the compound of the invention is an agent useful forthe treatment, prevention and/or prophylaxis of conditions, disorders ordiseases selected from the group consisting of the metabolic syndrome,insulin resistance, dyslipidemia, hypertension and obesity.

In one embodiment the compound of the invention is an agent useful forthe treatment, prevention and/or prophylaxis of type 2 diabetes,impaired glucose tolerance (IGT), impaired fasting glucose (IFG).

In one embodiment the compound of the invention is an agent useful forthe delaying or prevention of the progression from IGT into type 2diabetes.

In one embodiment the compound of the invention is an agent useful fordelaying or prevention of the progression of the metabolic syndrome intotype 2 diabetes.

In one embodiment the compound of the invention is an agent useful forthe treatment, prevention and/or prophylaxis of adverse effects ofglucocorticoid receptor agonist treatment or therapy.

In one aspect of the invention, the compounds according to the inventionhave a IC₅₀ value as tested as described under the heading“PHARMACOLOGICAL METHODS” below 1000 nM, in a further aspect below 500nM, in yet a further aspect below 300 nM and in yet a further aspectbelow 200 nM.

The compounds of the present invention have asymmetric centers and mayoccur as racemates, racemic mixtures, and as individual enantiomers ordiastereoisomers, with all isomeric forms being included in the presentinvention as well as mixtures thereof.

The present invention also encompasses pharmaceutically acceptable saltsof the present compounds. Such salts include pharmaceutically acceptableacid addition salts, pharmaceutically acceptable base addition salts,pharmaceutically acceptable metal salts, ammonium and alkylated ammoniumsalts. Acid addition salts include salts of inorganic acids as well asorganic acids. Representative examples of suitable inorganic acidsinclude hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric,nitric acids and the like. Representative examples of suitable organicacids include formic, acetic, trichloroacetic, trifluoroacetic,propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic,malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic,methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic,bismethylene salicylic, ethanedisulfonic, gluconic, citraconic,aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic,benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates,phosphates, perchlorates, borates, acetates, benzoates,hydroxyl-naphthoates, glycerophosphates, ketoglutarates and the like.Further examples of pharmaceutically acceptable inorganic or organicacid addition salts include the pharmaceutically acceptable salts listedin J. Pharm. Sci., 66, 2 (1977), which is incorporated herein byreference. Examples of metal salts include lithium, sodium, potassium,barium, calcium, magnesium, zinc, calcium salts and the like. Examplesof amines and organic amines include ammonium, methylamine,dimethylamine, trimethylamine, ethylamine, diethylamine, propylamine,butylamine, tetramethylamine, ethanolamine, diethanolamine,triethanolamine, meglumine, ethylenediamine, choline,N,N′-dibenzylethylenediamine, N-benzylphenyl-ethylamine,N-methyl-D-glucamine, guanidine and the like. Examples of cationic aminoacids include lysine, arginine, histidine and the like.

Further, some of the compounds of the present invention may formsolvates with water or common organic solvents. Such solvates areencompassed within the scope of the invention. The pharmaceuticallyacceptable salts are prepared by reacting a compound of the presentinvention with 1 to 4 equivalents of a base such as sodium hydroxide,sodium methoxide, sodium hydride, potassium tert-butoxide, calciumhydroxide, magnesium hydroxide and the like, in solvents like ether,THF, methanol, tert-butanol, dioxane, isopropanol, ethanol etc. Mixturesof solvents may be used. Organic bases like lysine, arginine,diethanolamine, choline, guandine and their derivatives etc. may also beused. Alternatively, acid addition salts wherever applicable areprepared by treatment with acids such as hydrochloric acid, hydrobromicacid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonicacid, methanesulfonic acid, acetic acid, citric acid, maleic acidsalicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid,succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and thelike in solvents like ethyl acetate, ether, alcohols, acetone, THF,dioxane etc. Mixture of solvents may also be used.

The stereoisomers of the compounds forming part of this invention may beprepared by using reactants in their single enantiomeric form in theprocess wherever possible or by conducting the reaction in the presenceof reagents or catalysts in their single enantiomer form or by resolvingthe mixture of stereoisomers by conventional methods. Some of thepreferred methods include use of microbial resolution, enzymaticresolution, resolving the diastereomeric salts formed with chiral acidssuch as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid,and the like wherever applicable or chiral bases such as brucine, (R)-or (S)-phenylethylamine, cinchona alkaloids and their derivatives andthe like. Commonly used methods are compiled by Jaques et al. in“Enantiomers, Racemates and Resolution” (Wiley Interscience, 1981). Morespecifically the compound of the present invention may be converted to a1:1 mixture of diastereomeric amides by treating with chiral amines,aminoacids, aminoalcohols derived from aminoacids; conventional reactionconditions may be employed to convert acid into an amide; thediastereomers may be separated either by fractional crystallization orchromatography and the stereoisomers of compound of formula I may beprepared by hydrolysing the pure diastereomeric amide.

Various polymorphs of the compounds forming part of this invention maybe prepared by crystallization of said compounds under differentconditions. For example, using different solvents commonly used or theirmixtures for recrystallization; crystallizations at differenttemperatures; various modes of cooling, ranging from very fast to veryslow cooling during crystallizations. Polymorphs may also be obtained byheating or melting the compound followed by gradual or fast cooling. Thepresence of polymorphs may be determined by solid probe nmrspectroscopy, it spectroscopy, differential scanning calorimetry, powderX-ray diffraction or such other techniques.

The invention also encompasses prodrugs of the present compounds, whichon administration undergo chemical conversion by metabolic processesbefore becoming active pharmacological substances. In general, suchprodrugs will be functional derivatives of the present compounds, whichare readily convertible in vivo into the required compound of thepresent invention. Conventional procedures for the selection andpreparation of suitable prodrug derivatives are described, for example,in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

It is a well known problem in drug discovery that compounds, such asenzyme inhibitors, may be very potent and selective in biochemicalassays, yet be inactive in vivo. This lack of so-called bioavailabilitymay be ascribed to a number of different factors such as lack of or poorabsorption in the gut, first pass metabolism in the liver and/or pooruptake in cells. Although the factors determining bioavailability arenot completely understood, there are many examples in the scientificliterature—well known to those skilled in the art—of how to modifycompounds, which are potent and selective in biochemical assays but showlow or no activity in vivo, into drugs that are biologically active.

It is within the scope of the invention to modify the compounds of thepresent invention, termed the ‘original compound’, by attaching chemicalgroups that will improve the bioavailability of said compounds in such away that the uptake in cells or mammals is facilitated.

Examples of said modifications, which are not intended in any way tolimit the scope of the invention, include changing of one or morecarboxy groups to esters (for instance methyl esters, ethyl esters,tert-butyl, acetoxymethyl, pivaloyloxymethyl esters or otheracyloxy-methyl esters). Compounds of the invention, original compounds,such modified by attaching chemical groups are termed ‘modifiedcompounds’.

The invention also encompasses active metabolites of the presentcompounds.

The compounds according to the invention alter, and more specifically,reduce the level of active intracellular glucocorticoid and areaccordingly useful for the treatment, prevention and/or prophylaxis ofdisorders and diseases in which such a modulation or reduction isbeneficial.

Accordingly, the present compounds may be applicable for the treatment,prevention and/or prophylaxis of the metabolic syndrome, insulinresistance, dyslipidemia, hypertension, obesity, type 2 diabetes,impaired glucose tolerance (IGT), impaired fasting glucose (IFG), LatentAutoimmune Diabetes in the Adult (LADA), type 1 diabetes, diabetic latecomplications including cardiovascular diseases, cardiovasculardisorders, disorders of lipid metabolism, neurodegenerative andpsychiatric disorders, dysregulation of intraocular pressure includingglaucoma, immune disorders, inappropriate immune responses,musculo-skeletal disorders, gastrointestinal disorders, polycysticovarie syndrome (PCOS), reduced hair growth or other diseases, disordersor conditions that are influenced by intracellular glucocorticoidlevels, adverse effects of increased blood levels of active endogenousor exogenous glucocorticoid, and any combination thereof, adverseeffects of increased plasma levels of endogenous active glucocorticoid,Cushing's disease, Cushing's syndrome, adverse effects of glucocorticoidreceptor agonist treatment of autoimmune diseases, adverse effects ofglucocorticoid receptor agonist treatment of inflammatory diseases,adverse effects of glucocorticoid receptor agonist treatment of diseaseswith an inflammatory component, adverse effects of glucocorticoidreceptor agonist treatment as a part of cancer chemotherapy, adverseeffects of glucocorticoid receptor agonist treatment forsurgical/post-surgical or other trauma, adverse effects ofglucocorticoid receptor agonist therapy in the context of organ ortissue transplantation or adverse effects of glucocorticoid receptoragonist treatment in other diseases, disorders or conditions whereglucocorticoid receptor agonists provide clinically beneficial effects.

More specifically the present compounds may be applicable for thetreatment, prevention and/or prophylaxis of the metabolic syndrome, type2 diabetes, diabetes as a consequence of obesity, insulin resistance,hyperglycemia, prandial hyperglycemia, hyperinsulinemia, inappropriatelylow insulin secretion, impaired glucose tolerance (IGT), impairedfasting glucose (IFG), increased hepatic glucose production, type 1diabetes, LADA, pediatric diabetes, dyslipidemia, diabetic dyslipidemia,hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia,hypercholesterolemia, decreased HDL cholesterol, impaired LDL/HDL ratio,other disorders of lipid metabolism, obesity, visceral obesity, obesityas a consequence of diabetes, increased food intake, hypertension,diabetic late complications, micro/macroalbuminuria, nephropathy,retinopathy, neuropathy, diabetic ulcers, cardiovascular diseases,arteriosclerosis, atherosclerosis, coronary artery disease, cardiachypertrophy, myocardial ischemia, heart insufficiency, congestionalheart failure, stroke, myocardial infarction, arrythmia, decreased bloodflow, erectile dysfunction (male or female), myopathy, loss of muscletissue, muscle wasting, muscle catabolism, osteoporosis, decreasedlinear growth, neurodegenerative and psychiatric disorders, Alzheimersdisease, neuronal death, impaired cognitive function, depression,anxiety, eating disorders, appetite regulation, migraine, epilepsia,addiction to chemical substances, disorders of intraocular pressure,glaucoma, polycystic ovary syndrome (PCOS), inappropriate immuneresponses, inappropriate T helper-1/T helper-2 polarisation, bacterialinfections, mycobacterial infections, fungal infections, viralinfections, parasitic infestations, suboptimal responses toimmunizations, immune dysfunction, partial or complete baldness, orother diseases, disorders or conditions that are influenced byintracellular glucocorticoid levels and any combination thereof, adverseeffects of glucocorticoid receptor agonist treatment ofallergic-inflammatory diseases such as asthma and atopic dermatitis,adverse effects of glucocorticoid receptor agonist treatment ofdisorders of the respiratory system e.g. asthma, cystic fibrosis,emphysema, bronchitis, hypersensitivity, pneumonitis, eosinophilicpneumonias, pulmonary fibrosis, adverse effects of glucocorticoidreceptor agonist treatment of inflammatory bowel disease such as Crohn'sdisease and ulcerative colitis; adverse effects of glucocorticoidreceptor agonist treatment of disorders of the immune system, connectivetissue and joints e.g. reactive arthritis, rheumatoid arthritis,Sjögren's syndrome, systemic lupus erythematosus, lupus nephritis,Henoch-Schönlein purpura, Wegener's granulomatosis, temporal arteritis,systemic sclerosis, vasculitis, sarcoidosis,dermatomyositis-polymyositis, pemphigus vulgaris; adverse effects ofglucocorticoid receptor agonist treatment of endocrinological diseasessuch as hyperthyroidism, hypoaldosteronism, hypopituitarism; adverseeffects of glucocorticoid receptor agonist treatment of hematologicaldiseases e.g. hemolytic anemia, thrombocytopenia, paroxysmal nocturnalhemoglobinuria; adverse effects of glucocorticoid receptor agonisttreatment of cancer such as spinal cord diseases, neoplastic compressionof the spinal cord, brain tumours, acute lymphoblastic leukemia,Hodgkin's disease, chemotherapy-induced nausea, adverse effects ofglucocorticoid receptor agonist treatment of diseases of muscle and atthe neuro-muscular joint e.g. myasthenia gravis and heriditarymyopathies (e.g. Duchenne muscular dystrophy), adverse effects ofglucocorticoid receptor agonist treatment in the context of surgery &transplantation e.g. trauma, post-surgical stress, surgical stress,renal transplantation, liver transplantation, lung transplantation,pancreatic islet transplantation, blood stem cell transplantation, bonemarrow transplantation, heart transplantation, adrenal glandtransplantation, tracheal transplantation, intestinal transplantation,corneal transplantation, skin grafting, keratoplasty, lens implantationand other procedures where immunosuppression with glucocorticoidreceptor agonists is beneficial; adverse effects of glucocorticoidreceptor agonist treatment of brain absess, nausea/vomiting, infections,hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, spinal corddiseases, saccular aneurysms or adverse effects to glucocorticoidreceptor agonist treatment in other diseases, disorders and conditionswhere glucocorticoid receptor agonists provide clinically beneficialeffects.

Accordingly, in a further aspect the invention relates to a compoundaccording to the invention for use as a pharmaceutical composition.

The invention also relates to pharmaceutical compositions comprising, asan active ingredient, at least one compound according to the inventiontogether with one or more pharmaceutically acceptable carriers ordiluents.

The pharmaceutical composition is preferably in unit dosage form,comprising from about 0.05 mg/day to about 2000 mg/day, preferably fromabout 1 mg/day to about 500 mg/day of a compound according to theinvention.

In another embodiment, the patient is treated with a compound accordingto the invention for at least about 1 week, for at least about 2 weeks,for at least about 4 weeks, for at least about 2 months or for at leastabout 4 months.

In yet another embodiment, the pharmaceutical composition is for oral,nasal, transdermal, pulmonal or parenteral administration.

Furthermore, the invention relates to the use of a compound according tothe invention for the preparation of a pharmaceutical composition forthe treatment, prevention and/or prophylaxis of disorders and diseaseswherein a modulation or an inhibition of the activity of 11βHSD1 isbeneficial.

The invention also relates to a method for the treatment, preventionand/or prophylaxis of disorders and diseases wherein a modulation or aninhibition of the activity of 11βHSD1 is beneficial, the methodcomprising administering to a subject in need thereof an effectiveamount of a compound according to the invention.

In a preferred embodiment of the invention the present compounds areused for the preparation of a medicament for the treatment, preventionand/or prophylaxis of any diseases and conditions that are influenced byintracellular glucocorticoid levels as mentioned above.

Thus, in a preferred embodiment of the invention the present compoundsare used for the preparation of a medicament for the treatment,prevention and/or prophylaxis of conditions and disorders where adecreased level of active intracellular glucocorticoid is desirable,such as the conditions and diseases mentioned above.

In yet a preferred embodiment of the invention the present compounds areused for the preparation of a medicament for the treatment, preventionand/or prophylaxis of the metabolic syndrome including insulinresistance, dyslipidemia, hypertension and obesity.

In yet another preferred embodiment of the invention the presentcompounds are used for the preparation of a medicament for thetreatment, prevention and/or prophylaxis of type 2 diabetes, impairedglucose tolerance (IGT), impaired fasting glucose (IFG).

In yet another preferred embodiment of the invention the presentcompounds are used for the preparation of a pharmaceutical compositionfor the delaying or prevention of the progression from IGT to type 2diabetes.

In yet another preferred embodiment of the invention the presentcompounds are used for the preparation of a pharmaceutical compositionfor the delaying or prevention of the progression of the metabolicsyndrome into type 2 diabetes.

In still another preferred embodiment of the invention the presentcompounds are used for the preparation of a pharmaceutical compositionfor the treatment, prevention and/or prophylaxis of diabetic latecomplications including cardiovascular diseases; arteriosclerosis;atherosclerosis.

In a further preferred embodiment of the invention the present compoundsare used for the preparation of a pharmaceutical composition for thetreatment, prevention and/or prophylaxis of neurodegenerative andpsychiatric disorders.

In yet a further preferred embodiment of the invention the presentcompounds are used for the preparation of a pharmaceutical compositionfor the treatment, prevention and/or prophylaxis of adverse effects ofglucocorticoid receptor agonist treatment or therapy.

In another embodiment of the present invention, the route ofadministration may be any route which effectively transports a compoundaccording to the invention to the appropriate or desired site of action,such as oral, nasal, buccal, transdermal, pulmonal, or parenteral.

In still a further aspect of the invention the present compounds areadministered in combination with one or more further active substancesin any suitable ratios. Such further active substances may e.g. beselected from antiobesity agents, antidiabetics, agents modifying thelipid metabolism, antihypertensive agents, glucocorticoid receptoragonists, agents for the treatment and/or prevention of complicationsresulting from or associated with diabetes and agents for the treatmentand/or prevention of complications and disorders resulting from orassociated with obesity.

Thus, in a further aspect of the invention the present compounds may beadministered in combination with one or more antiobesity agents orappetite regulating agents.

Such agents may be selected from the group consisting of CART (cocaineamphetamine regulated transcript) agonists, NPY (neuropeptide Y)antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF(tumor necrosis factor) agonists, CRF (corticotropin releasing factor)agonists, CRF BP (corticotropin releasing factor binding protein)antagonists, urocortin agonists, β3 agonists, MSH(melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentratinghormone) antagonists, CCK (cholecystokinin) agonists, serotoninre-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors,mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists,bombesin agonists, galanin antagonists, growth hormone, growth hormonereleasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DAagonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR(peroxisome proliferator-activated receptor) modulators, RXR (retinoid Xreceptor) modulators, TR β agonists, AGRP (Agouti related protein)inhibitors, H3 histamine antagonists, opioid antagonists (such asnaltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor.

In one embodiment of the invention the antiobesity agent is leptin;dexamphetamine or amphetamine; fenfluramine or dexfenfluramine;sibutramine; orlistat; mazindol or phentermine.

Suitable antidiabetic agents include insulin, insulin analogues andderivatives such as those disclosed in EP 792 290 (Novo Nordisk A/S),e.g. N^(εB29)-tetradecanoyl des (B30) human insulin, EP 214 826 and EP705 275 (Novo Nordisk A/S), e.g. Asp^(B28) human insulin, U.S. Pat. No.5,504,188 (Eli Lilly), e.g. Lys^(B28) Pro^(B29) human insulin, EP 368187 (Aventis), eg Lantus, which are all incorporated herein byreference, GLP-1 (glucagon like peptide-1) and GLP-1 derivatives such asthose disclosed in WO 98/08871 to Novo Nordisk A/S, which isincorporated herein by reference as well as orally active hypoglycaemicagents.

The orally active hypoglycaemic agents preferably comprisesulphonylureas, biguanides, meglitinides, glucosidase inhibitors,glucagon antagonists such as those disclosed in WO 99/01423 to NovoNordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassiumchannel openers such as those disclosed in WO 97/26265 and WO 99/03861to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV(dipeptidyl peptidase-IV) inhibitors, inhibitors of hepatic enzymesinvolved in stimulation of gluconeogenesis and/or glycogenolysis,glucose uptake modulators, compounds modifying the lipid metabolism suchas antihyperlipidemic agents and antilipidemic agents as PPARαmodulators, PPARδ modulators, cholesterol absorption inhibitors, HSL(hormone-sensitive lipase) inhibitors and HMG CoA inhibitors (statins),nicotinic acid, fibrates, anion exchangers, compounds lowering foodintake, bile acid resins, RXR agonists and agents acting on theATP-dependent potassium channel of the β-cells.

In one embodiment, the present compounds are administered in combinationwith insulin or an insulin analogue or derivative, such asN^(εB29)-tetradecanoyl des (B30) human insulin, Asp^(B28) human insulin,Lys^(B28) Pro^(B29) human insulin, Lantus®, or a mix-preparationcomprising one or more of these.

In a further embodiment the present compounds are administered incombination with a sulphonylurea e.g. tolbutamide, glibenclamide,glipizide or glicazide.

In another embodiment the present compounds are administered incombination with a biguanide e.g. metformin.

In yet another embodiment the present compounds are administered incombination with a meglitinide e.g. repaglinide or senaglinide.

In still another embodiment the present compounds are administered incombination with a thiazolidinedione e.g. troglitazone, ciglitazone,pioglitazone, rosiglitazone or compounds disclosed in WO 97/41097 suchas5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]-methoxy]phenyl-methyl]thiazolidine-2,4-dioneor a pharmaceutically acceptable salt thereof, preferably the potassiumsalt.

In yet another embodiment the present compounds may be administered incombination with the insulin sensitizers disclosed in WO 99/19313 suchas (−)3-[4-[2-Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid ora pharmaceutically acceptable salts thereof, preferably the argininesalt.

In a further embodiment the present compounds are administered incombination with an α-glucosidase inhibitor e.g. miglitol or acarbose.

In another embodiment the present compounds are administered incombination with an agent acting on the ATP-dependent potassium channelof the β-cells e.g. tolbutamide, glibenclamide, glipizide, glicazide orrepaglinide.

Furthermore, the present compounds may be administered in combinationwith nateglinide.

In still another embodiment the present compounds are administered incombination with an antihyperlipidemic agent or antilipidemic agent e.g.cholestyramine, colestipol, clofibrate, gemfibrozil, fenofibrate,bezafibrate, tesaglitazar, EML-4156, LY-818, MK-767, atorvastatin,fluvastatin, lovastatin, pravastatin, simvastatin, acipimox, probucol,ezetimibe or dextrothyroxine.

In a further embodiment the present compounds are administered incombination with more than one of the above-mentioned compounds e.g. incombination with a sulphonylurea and metformin, a sulphonylurea andacarbose, repaglinide and metformin, insulin and a sulphonylurea,insulin and metformin, insulin, insulin and lovastatin, etc.

Further, the present compounds may be administered in combination withone or more antihypertensive agents. Examples of antihypertensive agentsare 3-blockers such as alprenolol, atenolol, timolol, pindolol,propranolol, metoprolol, bisoprololfumerate, esmolol, acebutelol,metoprolol, acebutolol, betaxolol, celiprolol, nebivolol, tertatolol,oxprenolol, amusolalul, carvedilol, labetalol, β2-receptor blockers e.g.S-atenolol, OPC-1085, ACE (angiotensin converting enzyme) inhibitorssuch as quinapril, lisinopril, enalapril, captopril, benazepril,perindopril, trandolapril, fosinopril, ramipril, cilazapril, delapril,imidapril, moexipril, spirapril, temocapril, zofenopril, S-5590,fasidotril, Hoechst-Marion Roussel: 100240 (EP 00481522), omapatrilat,gemopatrilat and GW-660511, calcium channel blockers such as nifedipine,felodipine, nicardipine, isradipine, nimodipine, diltiazem, amlodipine,nitrendipine, verapamil, lacidipine, lercanidipine, aranidipine,cilnidipine, clevidipine, azelnidipine, barnidipine, efonodipine,iasidipine, iemildipine, iercanidipine, manidipine, nilvadipine,pranidipine, furnidipine, α-blockers such as doxazosin, urapidil,prazosin, terazosin, bunazosin and OPC-28326, diuretics such asthiazides/sulphonamides (e.g. bendroflumetazide, chlorothalidone,hydrochlorothiazide and clopamide), loop-diuretics (e.g. bumetanide,furosemide and torasemide) and potassium sparing diuretics (e.g.amiloride, spironolactone), endothelin ET-A antagonists such as ABT-546,ambrisetan, atrasentan, SB-234551, CI-1034, S-0139 and YM-598,endothelin antagonists e.g. bosentan and J-104133, renin inhibitors suchas aliskiren, vasopressin V1 antagonists e.g. OPC-21268, vasopressin V2antagonists such as tolvaptan, SR-121463 and OPC-31260, B-typenatriuretic peptide agonists e.g. Nesiritide, angiotensin II antagonistssuch as irbesartan, candesartancilexetil, losartan, valsartan,telmisartan, eprosartan, candesartan, CL-329167, eprosartan, iosartan,olmesartan, pratosartan, TA-606, and YM-358, 5-HT2 agonists e.g.fenoldopam and ketanserin, adenosine A1 antagonists such as naftopidil,N-0861 and FK-352, thromboxane A2 antagonists such as KT2-962,endopeptidase inhibitors e.g. ecadotril, nitric oxide agonists such asLP-805, dopamine D1 antagonists e.g. MYD-37, dopamine D2 agonists suchas nolomirole, n-3 fatty acids e.g. omacor, prostacyclin agonists suchas treprostinil, beraprost, PGE1 agonists e.g. ecraprost, Na+/K+ ATPasemodulators e.g. PST-2238, Potassium channel activators e.g. KR-30450,vaccines such as PMD-3117, Indapamides, CGRP-unigene, guanylate cyclasestimulators, hydralazines, methyldopa, docarpamine, moxonidine,CoAprovel, MondoBiotech-811.

Further reference can be made to Remington: The Science and Practice ofPharmacy, 19^(th) Edition, Gennaro, Ed., Mack Publishing Co., Easton,Pa., 1995.

Furthermore, the present compounds may be administered in combinationwith one or more glucocorticoid receptor agonists. Examples of suchglucocorticoid receptor agonists are betametasone, dexamethasone,hydrocortisone, methylprednisolone, prednisolone, prednisone,beclomethasone, butixicort, clobetasol, flunisolide, flucatisone (andanalogues), momethasone, triamcinolonacetonide, triamcinolonhexacetonideGW-685698, NXC-1015, NXC-1020, NXC-1021, NS-126, P-4112, P-4114,RU-24858 and T-25 series.

It should be understood that any suitable combination of the compoundsaccording to the invention with one or more of the above-mentionedcompounds and optionally one or more further pharmacologically activesubstances are considered to be within the scope of the presentinvention.

Pharmaceutical Compositions

The compounds of the present invention may be administered alone or incombination with pharmaceutically acceptable carriers or excipients, ineither single or multiple doses. The pharmaceutical compositionsaccording to the invention may be formulated with pharmaceuticallyacceptable carriers or diluents as well as any other known adjuvants andexcipients in accordance with conventional techniques such as thosedisclosed in Remington: The Science and Practice of Pharmacy, 19^(th)Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

The pharmaceutical compositions may be specifically formulated foradministration by any suitable route such as the oral, rectal, nasal,pulmonary, topical (including buccal and sublingual), transdermal,intracisternal, intraperitoneal, vaginal and parenteral (includingsubcutaneous, intramuscular, intrathecal, intravenous and intradermal)route, the oral route being preferred. It will be appreciated that thepreferred route will depend on the general condition and age of thesubject to be treated, the nature of the condition to be treated and theactive ingredient chosen.

Pharmaceutical compositions for oral administration include solid dosageforms such as hard or soft capsules, tablets, troches, dragees, pills,lozenges, powders and granules. Where appropriate, they can be preparedwith coatings such as enteric coatings or they can be formulated so asto provide controlled release of the active ingredient such as sustainedor prolonged release according to methods well-known in the art.

Liquid dosage forms for oral administration include solutions,emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration includesterile aqueous and non-aqueous injectable solutions, dispersions,suspensions or emulsions as well as sterile powders to be reconstitutedin sterile injectable solutions or dispersions prior to use. Depotinjectable formulations are also contemplated as being within the scopeof the present invention.

Other suitable administration forms include suppositories, sprays,ointments, crèmes, gels, inhalants, dermal patches, implants etc.

A typical oral dosage is in the range of from about 0.001 to about 100mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kgbody weight per day, and more preferred from about 0.05 to about 10mg/kg body weight per day administered in one or more dosages such as 1to 3 dosages. The exact dosage will depend upon the frequency and modeof administration, the sex, age, weight and general condition of thesubject treated, the nature and severity of the condition treated andany concomitant diseases to be treated and other factors evident tothose skilled in the art.

The formulations may conveniently be presented in unit dosage form bymethods known to those skilled in the art. A typical unit dosage formfor oral administration one or more times per day such as 1 to 3 timesper day may contain from 0.05 to about 2000 mg, e.g. from about 0.1 toabout 1000 mg, from about 0.5 mg to about 500 mg., from about 1 mg toabout 200 mg, e.g. about 100 mg.

For parenteral routes, such as intravenous, intrathecal, intramuscularand similar administration, typically doses are in the order of abouthalf the dose employed for oral administration.

The compounds of this invention are generally utilized as the freesubstance or as a pharmaceutically acceptable salt thereof. Examples arean acid addition salt of a compound having the utility of a free baseand a base addition salt of a compound having the utility of a freeacid. The term “pharmaceutically acceptable salts” refers to non-toxicsalts of the compounds for use according to the present invention whichare generally prepared by reacting the free base with a suitable organicor inorganic acid or by reacting the acid with a suitable organic orinorganic base. When a compound for use according to the presentinvention, contains a free base such salts are prepared in aconventional manner by treating a solution or suspension of the compoundwith a chemical equivalent of a pharmaceutically acceptable acid.

When a compounds for use according to the present invention, contains afree acid such salts are prepared in a conventional manner by treating asolution or suspension of the compound with a chemical equivalent of apharmaceutically acceptable base. Physiologically acceptable salts of acompound with a hydroxy group include the anion of said compound incombination with a suitable cation such as sodium or ammonium ion. Othersalts which are not pharmaceutically acceptable may be useful in thepreparation of compounds for use according to the present invention andthese form a further aspect of the present invention.

For parenteral administration, solutions of the present compounds insterile aqueous solution, aqueous propylene glycol or sesame or peanutoil may be employed. Such aqueous solutions should be suitable bufferedif necessary and the liquid diluent first rendered isotonic withsufficient saline or glucose. The aqueous solutions are particularlysuitable for intravenous, intramuscular, subcutaneous andintraperitoneal administration. The sterile aqueous media employed areall readily available by standard techniques known to those skilled inthe art.

Suitable pharmaceutical carriers include inert solid diluents orfillers, sterile aqueous solution and various organic solvents. Examplesof suitable carriers are water, salt solutions, alcohols, polyethyleneglycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil,syrup, phosphorlipids, gelatine, lactose, terra alba, sucrose,cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin,acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid,fatty acids, fatty acid amines, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, polyoxyethylene,hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrieror diluent may include any sustained release material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or mixedwith a wax. The formulations may also include wetting agents,emulsifying and suspending agents, preserving agents, sweetening agentsor flavouring agents.

The pharmaceutical compositions formed by combining the compounds of theinvention and the pharmaceutically acceptable carriers are then readilyadministered in a variety of dosage forms suitable for the disclosedroutes of administration. The formulations may conveniently be presentedin unit dosage form by methods known in the art of pharmacy.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules or tablets, eachcontaining a predetermined amount of the active ingredient, and whichmay include a suitable excipient. These formulations may be in the formof powder or granules, as a solution or suspension in an aqueous ornon-aqueous liquid, or as an oil-in-water or water-in-oil liquidemulsion.

Compositions intended for oral use may be prepared according to anyknown method, and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavouringagents, colouring agents, and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets may containthe active ingredient in admixture with non-toxicpharmaceutically-acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example corn starch or alginic acid; binding agents, for example,starch, gelatine or acacia; and lubricating agents, for examplemagnesium stearate, stearic acid or talc. The tablets may be uncoated orthey may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate may be employed. They mayalso be coated by the techniques described in U.S. Pat. Nos. 4,356,108;4,166,452; and 4,265,874, incorporated herein by reference, to formosmotic therapeutic tablets for controlled release.

Formulations for oral use may also be presented as hard gelatinecapsules where the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, ora soft gelatine capsule wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin, orolive oil.

Aqueous suspensions may contain the active compounds in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatidesuch as lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyl-eneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more colouring agents,one or more flavouring agents, and one or more sweetening agents, suchas sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as a liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active compound inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, flavouring, andcolouring agents may also be present.

The pharmaceutical compositions comprising a compound for use accordingto the present invention may also be in the form of oil-in-wateremulsions. The oily phase may be a vegetable oil, for example, olive oilor arachis oil, or a mineral oil, for example a liquid paraffin, or amixture thereof. Suitable emulsifying agents may be naturally-occurringgums, for example gum acacia or gum tragacanth, naturally-occurringphosphatides, for example soy bean, lecithin, and esters or partialesters derived from fatty acids and hexitol anhydrides, for examplesorbitan monooleate, and condensation products of said partial esterswith ethylene oxide, for example polyoxyethylene sorbitan monooleate.The emulsions may also contain sweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, preservative and flavouring and colouringagent. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known methods using suitable dispersing orwetting agents and suspending agents described above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conveniently employed as solvent or suspending medium. For thispurpose, any bland fixed oil may be employed using synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

The compositions may also be in the form of suppositories for rectaladministration of the compounds of the present invention. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will thus melt in the rectum torelease the drug. Such materials include cocoa butter and polyethyleneglycols, for example.

For topical use, creams, ointments, jellies, solutions of suspensions,etc., containing the compounds of the present invention arecontemplated. For the purpose of this application, topical applicationsshall include mouth washes and gargles.

The compounds for use according to the present invention may also beadministered in the form of liposome delivery systems, such as smallunilamellar vesicles, large unilamellar vesicles, and multilamellarvesicles. Liposomes may be formed from a variety of phospholipids, suchas cholesterol, stearylamine, or phosphatidylcholines.

In addition, some of the compounds for use according to the presentinvention may form solvates with water or common organic solvents. Suchsolvates are also encompassed within the scope of the present invention.

Thus, in a further embodiment, there is provided a pharmaceuticalcomposition comprising a compound for use according to the presentinvention, or a pharmaceutically acceptable salt, solvate, or prodrugthereof, and one or more pharmaceutically acceptable carriers,excipients, or diluents.

If a solid carrier is used for oral administration, the preparation maybe tabletted, placed in a hard gelatine capsule in powder or pellet formor it can be in the form of a troche or lozenge. The amount of solidcarrier will vary widely but will usually be from about 25 mg to about 1g. If a liquid carrier is used, the preparation may be in the form of asyrup, emulsion, soft gelatine capsule or sterile injectable liquid suchas an aqueous or non-aqueous liquid suspension or solution.

A typical tablet which may be prepared by conventional tablettingtechniques may contain:

Core: Active compound (as free compound or salt thereof) 5.0 mg LactosumPh. Eur. 67.8 mg Cellulose, microcryst. (Avicel) 31.4 mg Amberlite ®IRP88* 1.0 mg Magnesii stearas Ph. Eur. q.s. Coating: Hydroxypropylmethylcellulose approx. 9 mg Mywacett 9-40 T** approx. 0.9 mg*Polacrillin potassium NF, tablet disintegrant, Rohm and Haas.**Acylated monoglyceride used as plasticizer for film coating.

The compounds of the invention may be administered to a patient which isa mammal, especially a human in need thereof. Such mammals include alsoanimals, both domestic animals, e.g. household pets, and non-domesticanimals such as wildlife.

The present invention also relate to the below methods of preparing thecompounds of the invention.

The features disclosed in the foregoing description may, both separatelyand in any combination thereof, be material for realising the inventionin diverse forms thereof.

All references, including publications, patent applications and patents,cited herein are hereby incorporated by reference to the same extent asif each reference was individually and specifically indicated to beincorporated by reference and was set forth in its entirety herein.

All headings and sub-headings are used herein for convenience only andshould not be construed as limiting the invention in any way,

Any combination of the above-described elements in all possiblevariations thereof is encompassed by the invention unless otherwiseindicated herein or otherwise clearly contradicted by context.

The terms “a” and “an” and “the” and similar referents as used in thecontext of describing the invention are to be construed to cover boththe singular and the plural, unless otherwise indicated herein orclearly contradicted by context.

Recitation of ranges of values herein are merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range, unless otherwise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein. Unless otherwise stated, all exact valuesprovided herein are representative of corresponding approximate values(e.g., all exact exemplary values provided with respect to a particularfactor or measurement can be considered to also provide a correspondingapproximate measurement, modified by “about,” where appropriate).

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext.

The use of any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise indicated. No language in the specification should beconstrued as indicating any element is essential to the practice of theinvention unless as much is explicitly stated.

The citation and incorporation of patent documents herein is done forconvenience only and does not reflect any view of the validity,patentability and/or enforceability of such patent documents,

The description herein of any aspect or embodiment of the inventionusing terms such as “comprising”, “having”, “including” or “containing”with reference to an element or elements is intended to provide supportfor a similar aspect or embodiment of the invention that “consists of”,“consists essentially of”, or “substantially comprises” that particularelement or elements, unless otherwise stated or clearly contradicted bycontext (e.g., a formulation described herein as comprising a particularelement should be understood as also describing a formulation consistingof that element, unless otherwise stated or clearly contradicted bycontext).

This invention includes all modifications and equivalents of the subjectmatter recited in the aspects or claims presented herein to the maximumextent permitted by applicable law.

The present invention is further illustrated in the followingrepresentative examples which are, however, not intended to limit thescope of the invention in any way. The following examples and generalprocedures refer to intermediate compounds and final products forgeneral formula (I)

EXAMPLES

The following examples and general procedures refer to intermediatecompounds and final products for general formula (I) identified in thespecification and in the synthesis schemes. The preparation of thecompounds of general formula (I) of the present invention is describedin detail using the following examples. Occasionally, the reaction maynot be applicable as described to each compound included within thedisclosed scope of the invention. The compounds for which this occurswill be readily recognised by those skilled in the art. In these casesthe reactions can be successfully performed by conventionalmodifications known to those skilled in the art, which is, byappropriate protection of interfering groups, by changing to otherconventional reagents, or by routine modification of reactionconditions. Alternatively, other reactions disclosed herein or otherwiseconventional will be applicable to the preparation of the correspondingcompounds of the invention. In all preparative methods, all startingmaterials are known or may easily be prepared from known startingmaterials. The structures of the compounds are confirmed by eitherelemental analysis or nuclear magnetic resonance (NMR), where peaksassigned to characteristic protons in the title compounds are presentedwhere appropriate. ¹H NMR shifts (δ_(H)) are given in parts per million(ppm) down field from tetramethylsilane as internal reference standard.M.p.: is melting point and is given in ° C. and is not corrected. Columnchromatography was carried out using the technique described by W. C.Still et al., J. Org. Chem. 43: 2923 (1978) on Merck silica gel 60 (Art.9385). HPLC analyses are performed using 5 μm C18 4×250 mm column elutedwith various mixtures of water and acetonitrile, flow=1 ml/min, asdescribed in the experimental section.

Preparative HPLC: Column:

1.9×15 cm Waters XTerra RP-18. Buffer: linear gradient 5-95% MeCN inwater over 15 min, 0.1% TFA, flow rate of 15 ml/min. The pooledfractions are either evaporated to dryness in vacuo, or evaporated invacuo until the MeCN is removed, and then frozen and freeze dried.

The abbreviations as used in the examples have the following meaning:

-   ADDP: 1,1′-(Azodicarbonyl)dipiperidine-   CDCl₃: Deuterio chloroform-   DCM: Dichloromethane-   DEAD: 1,1′-Diethyl azodicarboxylate-   DIAD: 1,1′-Disopropyl azodicarboxylate-   DIC: N,N′-Diisopropylcarbodiimide-   DMAP: 4-Dimethylaminopyridine-   DMF: N,N-Dimethylformamide-   DMSO-d₆: Hexadeuterio dimethylsulfoxide-   DMSO: Dimethylsulfoxide-   DIPEA: Diisopropylethylamine-   EDC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   EtOAc: Ethyl acetate-   HOBT: 1-Hydroxy-benzotriazole-   hrs: hours-   MeCN: Acetonitrile-   min: minutes-   NMP: N-Methylpyrrolidinone-   TBAF: Tetrabutyl ammoniumfluoride-   TEA: Triethylamine-   TFA: Trifluoroacetic acid-   THF: Tetrahydrofuran-   TLC: Thin layer chromatography    General Method A:

By allowing an acid (I) wherein R⁴, R⁵, and Y are defined as above to becoupled with an amine (II) wherein R¹ and R² are defined as above understandard amide bond forming conditions using a coupling reagent (e.g.HOBT, EDC and DIPEA in dry DMF) affording amide (III) wherein R¹, R²,R⁴, R⁵, and Y are defined as above. Amines (II) are used as singleisomers of as mixtures of two isomer, therefore amides (III) areisolated as mixtures of two isomers or as single isomers.

General Method B:

By allowing an acid (I) wherein R⁴, R⁵, and Y are defined as above toform the corresponding acid chloride by reaction with thionyl chloride,and then reacting the acid chloride with an amine (II) wherein R¹ and R²are defined as above under basic conditions (eg. triethyl amine, DIPEA,K₂CO₃ and the like) in a solvent (DCM, DMF, THF, NMP and the like)affording amide (III) wherein R¹, R², R⁴, R⁵, and Y are defined asabove. Amines (II) are used as single isomers of as mixtures of twoisomer, therefore amides (III) are isolated as mixtures of two isomersor as single isomers.

Alternatively, the acid chloride corresponding to acid (I) wherein R⁴,R⁵, and Y are defined as above can be used directly to react with amine(II) wherein R¹ and R² are defined as above under similar basicconditions.

General Method C:

By allowing an alcohol (I) wherein Y is defined as above to be coupledwith an benzoic acid ester (II) wherein R is a C₁-C₄alkyl and R⁴ and R⁵are defined as above under standard Mitsunobu conditions using aphosphine reagent (e.g. triphenylphosphine or tributylphosphine)together with a diazocarbonyl reagent (e.g. DEAD, DIAD, ADDP) in asolvent (e.g. THF, dioxane, DCM) followed by standard alkalinehydrolysis (using a strong base such as NaH, NaOH and the like)affording acid (III) wherein R⁴, R⁵, and Y are defined as above.

IUPAC Molecule LC-MS (m/z) N-(5-Hydroxy-adamantan-2-yl)-N-methyl-3-phenethyloxy-benzamide

407 (M + 1) N-(5-Hydroxy-adamantan-2-yl)-3- phenethyloxy-benzamide

393 (M + 1) 3-Cyclohexylmethoxy-N-(5-hydroxy-adamantan-2-yl)-N-methyl-benzamide

399 (M + 1) N-(5-Hydroxy-adamantan-2-yl)-N-methyl-3-(1-methyl-butoxy)-benzamide

373 (M + 1) N-(5-Hydroxy-adamantan-2-yl)-3- methoxy-N-methyl-benzamide

316 (M + 1) N-(5-Hydroxy-adamantan-2-yl)-N-methyl-3-(2-pyridin-2-yl-ethoxy)- benzamide

408 (M + 1) N-(5-Hydroxy-adamantan-2-yl)-3-(2-pyridin-2-yl-ethoxy)-benzamide

394 (M + 1) 3-Benzyloxy-N-(5-hydroxy-adamantan- 2-yl)-benzamide

379 (M + 1) N-(5-Hydroxy-adamantan-2-yl)-3-(2-morpholin-4-yl-ethoxy)-benzamide

402 (M + 1) 4-{2-[3-(5-Hydroxy-adamantan-2-ylcarbamoyl)-phenoxy]-ethyl}- piperidine-1-carboxylic acidisopropylamide

485 (M + 1) 3-[2-(1-Cyclopropanesulfonyl-piperidin-4-yl)-ethoxy]-N-(5-hydroxy-adamantan- 2-yl)-benzamide

504 (M + 1) 3-(6-Chloro-pyridin-3-ylmethoxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide

413 (M) N-(5-Hydroxy-adamantan-2-yl)-3- (tetrahydro-pyran-4-ylmethoxy)-benzamide

386 (M) N-(5-Hydroxy-adamantan-2-yl)-3-[2-(tetrahydro-pyran-4-yl)-ethoxy]- benzamide

400 (M) N-(5-Hydroxy-adamantan-2-yl)-3-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-benzamide

400 (M + 1) N-(5-Hydroxy-adamantan-2-yl)-N-methyl-3-(tetrahydro-pyran-4-yloxy)- benzamide

387 (M + 1) (3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-[3-(tetrahydro-pyran-4-ylmethoxy)- phenyl]-methanone

346 (M + 1) (3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-{3-[2-(tetrahydro-pyran-4-yl)- ethoxy]-phenyl}-methanone

360 (M) (3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-[3-(4-hydroxy-cyclohexylmethoxy)- phenyl]-methanone

360 (M + 1)

Example 1 Ethyl 3-cyclohexylmethoxy-benzoate

Cyclohexyl methanol (2.0 g, 17.5 mmol), ethyl 3-hydroxybenzoate (2.6 g,15.8 mmol), tri-n-butyl phosphin (5.3 g, 26 mmol), and ADDP (6.6 g, 26mmol) were dissolved in dry THF (100 ml) and stirred overnight at 20° C.under N₂. Water (100 ml) is added, and the resulting solution isextracted with DCM (3×100 ml). The combined organic layers were washedwith water (100 ml), dried (MgSO₄) and evaporated. The crude mixture waspurified by preparative HPLC to give 1.8 g of the title compound. LC-MS(m/z): 264 (M+2).

3-Cyclohexylmethoxy-benzoic Acid

Ethyl 3-cyclohexylmethoxy benzoic acid (1.8 g, 6.7 mmol) was dissolvedin ethanol (50 ml) and THF (50 ml), whereupon NaOH (4 N, 10 ml) wasadded, and the solution was stirred overnight at 20° C. To the reactionmixture was added HCl (2 N, 200 ml), and the resulting solution wasextracted with DCM (3×100 ml). The combined organic extracts were washedwith water (100 ml), dried (MgSO₄) and evaporated to give 1.6 g of thetitle compound. LC-MS (m/z): 236 (M+2).

The following compounds were prepared by a method similar to Example 1

3-Phenethyloxy-benzoic Acid

Prepared from 2-phenethylalcohol and ethyl 3-hydroxybenzoate. LC-MS(m/z): 265 (M+22 (Na)).

3-(Tetrahydro-pyran-4-ylmethoxy)-benzoic Acid

Prepared from tetrahydro-2H-pyran-4-yl-methanol and ethyl3-hydroxybenzoate.

3-[2-(Tetrahydro-pyran-4-yl)-ethoxy]-benzoic acid

Prepared from tetrahydro-2H-pyran-4-yl-ethanol and ethyl3-hydroxybenzoate.

3-(Tetrahydro-pyran-4-yloxy)-benzoic Acid

Prepared from 4-hydroxy-tetrahydropyrane and ethyl 3-hydroxybenzoate.LC-MS (m/z): 245 (M−23 (Na)).

Example 2 [4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-methanol

tert-Butyldimethylsilyl chloride (8.8 g, 58 mmol) was added to asolution of ethyl 4-hydroxycyclohexanecarboxylate (10 g, 58 mmol) andimidazole (4.3 g, 64 mmol) in DCM (300 ml), and the mixture was stirredovernight at 20° C. After washing with water (2×100 ml), the organicphase was dried (MgSO₄) and evaporated to dryness. The residue wasdissolved in dry THF (300 ml) and cooled to −10° C. Dibal-H (1.0 M intoluene, 174 ml, 174 mmol) was added dropwise over a period of 60 min,while the temperature was kept at −10° C. After stirring for 2 hrs thereaction was quenched by slow addition of a saturated ammonium chloridesolution (30 ml). The resulting suspension was filtered, and thefiltrate was concentrated in vacuo to give 13 g of the title compound asa mixture of two isomers. LC-MS (m/z): 245 (M+1).

3-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexylmethoxy]-benzoic Acid

Prepared from [4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-methanoland ethyl 3-hydroxybenzoate by a method similar to Example 1.

Example 3 N-Boc-3-(2-piperidin-4-yl-ethoxy)-benzoic Acid Ethyl Ester

N-Boc-4-piperidine ethanol (15 g, 65 mmol) and ethyl 3-hydroxybenzoate(11 g, 65 mmol) were dissolved in dry THF (750 ml) under N₂. To this wasadded tri-n-butylphosphin (24 ml, 98 mmol) and ADDP (25 g, 98 mmol)resulting in a suspension, which was stirred overnight at 20° C. Themixture was concentrated in vacuo to 100 ml, filtered, and the filtratewas evaporated with silica gel. Flash chromatography (EtOAc/heptane 1:4)afforded 24 g of the title compound. LC-MS (m/z): 401 (M+23).

Ethyl 3-(2-piperidin-4-yl-ethoxy)-benzoate

TFA (25 ml) was added to a solution ofN-Boc-3-(2-piperidin-4-yl-ethoxy)-benzoic acid ethyl ester (8.5 g, 22mmol) in DCM (100 ml). Stirring overnight followed by evaporation of thesolvents afforded 10 g of the title compound as the TFA salt. LC-MS(m/z): 279 (M+1).

Ethyl 3-[2-(1-isopropylcarbamoyl-piperidin-4-yl)-ethoxy]-benzoate

Ethyl 3-(2-piperidin-4-yl-ethoxy)-benzoate (1.0 g of the TFA salt, 2.6mmol) was dissolved in DCM (10 ml), whereupon DIPEA (1.3 ml, 7.7 mmol)and isopropyl isocyanate (0.33 g, 3.8 mmol) was added. The reactionmixture was shaken overnight at 20° C. Silica gel (10 ml) was added, andthe solvent removed in vacuo. Flash chromatography (EtOAc/heptan 35:6555:45) provided 0.67 g of the title compound. LC-MS (m/z): 364 (M+2).

3-[2-(1-Isopropylcarbamoyl-piperidin-4-yl)-ethoxy]-benzoic Acid

Ethyl 3-[2-(1-isopropylcarbamoyl-piperidin-4-yl)-ethoxy]-benzoate (0.67g, 1.8 mmol) was dissolved in ethanol (25 ml), whereupon NaOH (1 N, 10ml) was added, and the solution was stirred overnight at 20° C. Thereaction mixture was concentrated in vacuo, dissolved in HCl (1 N, 25ml) and the resulting solution was extracted with EtOAc (3×25 ml). Thecombined organic extracts were dried (MgSO₄) and evaporated to give 0.62of the title compound. LC-MS (m/z): 336 (M+2).

The following compound was prepared by a method similar to Example 3with the variation stated.

3-[2-(1-cyclopropanesulfonyl-piperidin-4-yl)-ethoxy]-benzoic Acid

Prepared from N-Boc-4-piperidine ethanol and ethyl 3-hydroxybenzoate,with the exception that ethyl 3-(2-piperidin-4-yl-ethoxy)-benzoate wasconverted to its corresponding sulfonamide as described below before thefinal alkaline hydrolysis to give the title compound. LC-MS (m/z): 377(M+23 (Na)).

Sulfonamide Formation

DIPEA (1.3 ml, 7.7 mmol) was added to a solution of ethyl3-(2-piperidin-4-yl-ethoxy)-benzoate (1.0 g of the TFA salt, 2.6 mmol)in DCM (10 ml). After shaking for 5 min cyclopropanesulfonyl chloride(0.54 g, 3.8 mmol) was added and the reaction mixture was shakenovernight at 20° C. After addition of silica gel (10 ml) the solvent wasremoved in vacuo, and flash chromatography (EtOAc/heptan 30:70 50:50)gave 0.71 g of the desired sulfonamide.

Example 4 3-(6-Chloro-pyridin-3-ylmethoxy)-benzoic Acid

NaH (55% suspension in mineral oil, 1.2 g, 28 mmol) was slowly added toa suspension of 2-chloro-5-chloromethylpyridine (3.0 g, 19 mmol), ethyl3-hydroxybenzoate (3.1 g, 19 mmol), and potassium iodide (600 mg, 3.7mmol) in DMF (20 ml). After stirring for 2 days at 20° C., water (10 ml)and NaOH (32.5%, 2 ml) was added. The dark mixture was stirred at 80° C.overnight, whereupon it was concentrated in vacuo. The residue waspurified by preparative LC-MS to give 0.80 g of the title compound.LC-MS (m/z): 264 (M+1).

The following compounds were prepared by a method similar to Example 4

3-(5-Chloro-pyridin-2-yloxy)-benzoic Acid

Prepared from 2,5-dichloropyridine and ethyl 3-hydroxybenzoate. ¹H NMR(400 MHz, DMSO-d₅) δ 13.17 (br. s., 1H), 8.22 (d, 1H), 8.00 (dd, 1H),7.81 (dd, 1H), 7.60-7.64 (m, 1H), 7.58 (t, 1H), 7.43 (dd, 1H), 7.18 (d,1H).

3-(6-Bromo-pyridin-3-yloxy)-benzoic Acid

Prepared from 2-bromo-5-fluoropyridine and ethyl 3-hydroxybenzoate. ¹HNMR (400 MHz, DMSO-d₆) δ 13.12 (br. s., 1H), 8.28 (d, 1H), 7.78 (d, 1H),7.69 (d, 1H), 7.56 (t, 1H), 7.48-7.54 (m, 2H), 7.39 (dd, 1H)

Example 5 4-Amino-1-hydroxyadamantane

Prepared as described in Tetrahedron 1968, 24, 5369

Example 6 (5-Hydroxyadamantan-2-yl)carbamic Acid Tert-butyl Ester

Ammonium formate (10 g, 0.15 mol) was added to a solution of5-hydroxyadamantan-2-one (4.5 g, 0.027 mol, prepared as described inTetrahedron 1968, 24, 5369) in MeOH (50 ml). Then 10% Pd—C (500 mg) wasadded carefully and the solution heated under reflux for 1 h. It wasthen filtered through celite and to this filtrate at 0° C. was addedtriethylamine (11.2 ml, 0.081 mol) and Boc anhydride (7.06 g, 0.0324mol). The solution was stirred for 4 h at 20° C. and then concentratedunder reduced pressure. The residue was diluted with water and extractedwith EtOAc. The organic layer was dried and concentrated to give(5-hydroxyadamantan-2-yl)carbamic acid tert-butyl ester (7 g, 96%).LC-MS (m/z): 168 (M+1). ¹H NMR (300 MHz, DMSO-d₆): δ 6.8 (d, 1H), 6.7(brs, 1H), 3.45 (d, 1H), 2.0 (s, 1H), 1.75-1.95 (m, 4H), 1.5-1.7 (m,6H), 1.35 (s, 9H), 1.25 (t, 2H).

1-Hydroxy-4-methylamino-adamantane

Lithium aluminium hydride (0.711 g, 0.018 mol) was added to a solutionof (5-hydroxy-adamantan-2-yl)carbamic acid tert-butyl ester (1 g, 0.0037mol) in THF (50 ml) at 0° C. under a nitrogen atmosphere. The slurry washeated under reflux for 5 h. It was then cooled to 0° C. and quenchedwith 30% NaOH solution (12 ml) and filtered. The filtrate wasconcentrated to give 2-methylaminoadamantan-5-ol as a white solid (0.6g, 90%). LC-MS (m/z): 181.9 (M+1). ¹H NMR (300 MHz, DMSO-d₆): δ 4.3 (s,1H), 4.2 (s, 1H), 2.4 (s, 0.7H), 2.3 (s, 0.3H), 2.2 (s, 3H), 1.8-2.0 (m,5H), 1.5-1.6 (m, 5H), 1.4-1.5 (m, 2H), 1.2 (m, 2H).

Example 7 3-Oxo-8-azabicyclo[3.2.1]octane-8-carboxylic Acid Tert-butylEster

Nortropinone (10 g, 0.062 mol) was dissolved in DCM (100 ml) andtriethylamine (13.5 ml, 0.13 mol) was added followed by Boc anhydride(21.8 g, 0.10 mol). The reaction mixture was stirred at 20° C. for 3 h.It was then diluted with DCM (60 ml) and washed with 1N HCl, then twicewith water and finally with brine. The organic layer was dried overanhydrous sodium sulphate and was concentrated under vacuum to give 15 g(86%) of 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butylester. ¹H NMR (300 MHz, DMSO-d₆): δ 4.2 (1H, s), 2.3 (2H, brs), 2.2 (2H,d), 2.0 (2H, brs), 1.6 (2H, d), 1.4 (9H, m).

3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic Acid tert-butyl Ester

NaBH₄ (8.8 g, 0.23 mol) was added to a 0° C. solution of3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (35g, 0.16 mol) in ethanol (200 ml). The reaction mixture was stirred for45 min at 0° C., whereupon it was allowed to reach 20° C. After stirringovernight the suspension was evaporated to dryness. EtOAc (350 ml) wasadded, and the precipitate was filtered off. Water (200 ml) was added tothe filtrate, and the layers were separated. The aqueous layer wasextracted with EtOAc (100 ml), and the combined organic layers weredried (Na₂SO₄) and concentrated in vacuo to afford 29.5 g of an oil,which crystallised on standing. The two isomers were separated by flashchromatography (EtOAc/heptane 1:5 1:1), affording 5 g of the titlecompound. LC-MS (m/z): 250 (M+23 (Na)).

(1R,3S,5S)-8-Aza-bicyclo[3.2.1]octan-3-ol

HCl (conc. 10 ml) was added to a solution of3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester(2.1 g, 9.2 mmol) in ethanol (30 ml). After stirring for 5 h the solventwas removed in vacuo to give 1.4 g of the title compound. LC-MS (m/z):127 (M+1).

Example 83-Cyclohexylmethoxy-N-(5-hydroxy-adamantan-2-yl)-N-methyl-benzamide

3-Cyclohexylmethoxy-benzoic acid (300 mg, 1.3 mmol), HOBT (294 mg, 1.9mmol), EDC (245 mg, 1.3 mmol), and 1-hydroxy-4-methylaminoadamantane(232 mg, 1.28 mmol) were suspended in DMF (2.5 ml) before DIPEA (0.44ml, 2.6 mmol) was added. The reaction mixture was stirred at 20° C.overnight. The reaction mixture was purified directly by PreparativeHPLC to give 199 mg of the title compound as a mixture of two isomers.

¹H NMR (400 MHz, CDCl₃) δ: 7.24-7.32 (m, 1H), 6.88-6.98 (m, 3H),4.10-4.24 (m, 1H), 3.76 (d, 1H), 3.10 (s, 3H), 2.51 (br. s., 2H), 2.23(br. s., 2H), 1.63-2.02 (m, 14H), 1.57 (d, 2H), 1.16-1.36 (m, 3H),0.98-1.11 (m, 2H).

The following compounds were prepared by a method similar to Example 8.

4-{2-[3-(5-Hydroxy-adamantan-2-ylcarbamoyl)-phenoxy]-ethyl}-piperidine-1-carboxylicAcid isopropylamide

Prepared from 3-[2-(1-isopropylcarbamoyl-piperidin-4-yl)-ethoxy]-benzoicacid and 4-amino-1-hydroxyadamantane. ¹H NMR (400 MHz, CDCl₃): δ7.31-7.37 (m, 2H), 7.23-7.26 (m, 1H), 7.04 (dd, 1H), 6.37 (d, 1H),4.18-4.24 (m, 1H), 4.06 (t, 2H), 3.98 (septet, 1H), 3.90 (d, 2H), 2.82(t, 2H), 2.17-2.29 (m, 3H), 1.92-1.99 (m, 2H), 1.73-1.86 (m, 11H), 1.59(d, 2H), 1.19-1.30 (m, 2H), 1.16 (d, 6H).

3-[2-(1-Cyclopropanesulfonyl-piperidin-4-yl)-ethoxy]-N-(5-hydroxy-adamantan-2-yl)-benzamide

Prepared from3-[2-(1-cyclopropanesulfonyl-piperidin-4-yl)-ethoxy]-benzoic acid and4-amino-1-hydroxyadamantane. ¹H NMR (400 MHz, CDCl₃): δ 7.32-7.38 (m,2H), 7.24-7.26 (m, 1H), 7.03 (dd, 1H), 6.32 (d, 1H), 4.19-4.24 (m, 1H),4.07 (t, 2H), 3.78-3.85 (m, 2H), 2.81 (td, 2H), 2.61 (br. s., 2H),2.22-2.29 (m, 3H), 2.18-2.22 (m, 1H), 1.95 (d, 2H), 1.73-1.89 (m, 11H),1.65-1.73 (m, 1H), 1.59 (d, 2H), 1.41 (dd, 1H), 1.35 (dd, 1H), 1.14-1.20(m, 2H), 0.94-1.00 (m, 2H).

3-(6-Chloro-pyridin-3-ylmethoxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide

Prepared from 3-(6-chloro-pyridin-3-ylmethoxy)-benzoic acid and4-amino-1-hydroxyadamantane. ¹H NMR (400 MHz, CDCl₃): δ 8.49 (d, 1H),7.78 (dd, 1H), 7.42-7.44 (m, 1H), 7.38 (t, 2H), 7.32 (d, 1H), 7.10 (dd,1H), 6.32 (d, 1H), 5.12 (s, 2H), 4.19-4.24 (m, 1H), 3.13 (br. s., 2H),2.26 (br. s., 2H), 2.21 (br. s., 1H), 1.95 (d, 2H), 1.73-1.85 (m, 6H),1.59 (d, 2H).

N-(5-Hydroxy-adamantan-2-yl)-3-(tetrahydro-pyran-4-ylmethoxy)-benzamide

Prepared from 3-(tetrahydro-pyran-4-ylmethoxy)-benzoic acid and4-amino-1-hydroxyadamantane. LC-MS (m/z): 386 (M+1).

N-(5-Hydroxy-adamantan-2-yl)-3-[2-(tetrahydro-pyran-4-yl)-ethoxy]-benzamide

Prepared from 3-(tetrahydro-pyran-4-ylethoxy)-benzoic acid and4-amino-1-hydroxyadamantane. LC-MS (m/z): 400 (M).

N-(5-Hydroxy-adamantan-2-yl)-3-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-benzamide

Prepared from pyrrolidinoneethoxy-benzoic acid and4-amino-1-hydroxyadamantane. LC-MS (m/z): 400 (M+1).

N-(5-Hydroxy-adamantan-2-yl)-N-methyl-3-(tetrahydro-pyran-4-yloxy)-benzamide

Prepared from 3-(tetrahydro-pyran-4-yloxy)-benzoic acid and1-hydroxy-4-methylaminoadamantane. LC-MS (m/z): 387 (M+2).

3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-[3-(tetrahydro-pyran-4-ylmethoxy)-phenyl]-methanone

Prepared from 3-(tetrahydro-pyran-4-yl-methoxy)-benzoic acid and8-aza-bicyclo[3.2.1]octan-3-ol. LC-MS (m/z): 346 (M+1).

(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-{3-[2-(tetrahydro-pyran-4-yl)-ethoxy]-phenyl}-methanone

Prepared from 3-(tetrahydro-pyran-4-yl-ethoxy)-benzoic acid and8-aza-bicyclo[3.2.1]octan-3-01. LC-MS (m/z): 360 (M).

3-(4-Fluoro-benzyloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide

Prepared from 3-(4-fluoro-benzyloxy)-benzoic acid and4-amino-1-hydroxyadamantane. LC-MS (m/z): 296 (M+1).

3-(5-Chloro-pyridin-2-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide

Prepared from 3-(5-chloro-pyridin-2-yloxy)-benzoic acid and4-amino-1-hydroxyadamantane. ¹H NMR (400 MHz, CDCl₃): δ 8.11 (s, 1H),7.68 (d, 1H), 7.51-7.61 (m, 2H), 7.47 (t, 1H), 6.94 (d, 1H), 6.23-6.36(m, 1H), 4.08-4.25 (m, 1H), 2.24 (t, 3H), 1.51-2.03 (m, 13H).

3-(6-Bromo-pyridin-3-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide

Prepared from 3-(6-bromo-pyridin-3-yloxy)-benzoic acid and4-amino-1-hydroxyadamantane. LC-MS (m/z): 444 (M+1).

(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-[3-(4-hydroxy-cyclohexylmethoxy)-phenyl]-methanone

Prepared from3-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexylmethoxy]-benzoic acidand 8-Aza-bicyclo[3.2.1]octan-3-ol by a method similar to Example 8followed by desilylation:

Desilylation

The partly desilylated product from the coupling reaction was dissolvedin dry THF (20 ml), and after addition of TBAF (1.0 M in THF, 0.83 ml)the solution was allowed to stir overnight at 20° C. Addition of citricacid (5% in water, 25 ml) and extraction with EtOAc (3×25 ml), followedby drying (MgSO₄) and evaporation of the combined organic layersafforded the crude product. This was purified by preparative HPLC togive 170 mg of the title compound as a mixture of four isomers. ¹H NMR(400 MHz, CDCl₃): δ 7.27-7.33 (m, 1H), 6.93-7.03 (m, 3H), 4.78-4.90 (m,1H), 4.03-4.24 (m, 2H), 3.75-3.85 (m, 2H), 2.81 (br. s., 4H), 1.07-2.36(m, 19H).

Example 9 N-(5-Hydroxy-adamantan-2-yl)-N-methyl-3-phenethyloxy-benzamide

3-Phenethyloxy-benzoic acid (4.2 g, 17 mmol) was dissolved inthionylchloride (30 ml), and the mixture was stirred at 20° C.overnight. The solvent was removed, and 108 mg (0.41 mmol) of this acidchloride was added to a solution of 1-hydroxy-4-methylaminoadamantane(75 mg, 0.41 mmol) and DIPEA (0.14 ml, 0.83 mmol) in DCM/DMF (1:1, 4ml). After stirring the reaction mixture at 20° C. overnight, thesolution was concentrated in vacuo and purified by preparative LC-MS togive 95 mg of the title compound as a mixture of two isomers. ¹H NMR(400 MHz, CDCl₃): δ 7.21-7.36 (m, 6H), 6.89-7.00 (m, 3H), 4.10-4.23 (m,3H), 3.05-3.16 (m, 5H), 2.54 (d, 2H), 2.24 (d, 1H), 1.49-2.04 (m, 11H).

The following compounds were prepared by a method similar to Example 9.

N-(5-Hydroxy-adamantan-2-yl)-3-phenethyloxy-benzamide

Prepared from 3-phenethyloxy-benzoic acid and4-amino-1-hydroxyadamantane to give the title compound as a mixture oftwo isomers. ¹H NMR (300 MHz, CDCl₃): δ 7.20-7.39 (m, 8H), 7.13 (dd,0.3H), 7.02 (dd, 0.7H), 6.22-6.38 (m, 1H), 4.09-4.28 (m, 3H), 3.11 (t,2H), 2.24 (t, 2H), 1.47-2.00 (m, 9H).

3-Benzyloxy-N-(5-hydroxy-adamantan-2-yl)-benzamide

Prepared from 3-(benzyloxy)benzoic acid and 4-amino-1-hydroxyadamantaneto give the title compound as a mixture of two isomers. ¹H NMR (300 MHz,CDCl₃): δ 7.69-7.74 (m, 1H), 7.29-7.48 (m, 7H), 7.20-7.24 (m, 0.5H),7.09-7.13 (m, 0.5H), 6.27 (d, 1H), 5.12 (s, 2H), 4.18-4.23 (m, 1H),2.16-2.27 (m, 3H), 1.91-1.98 (m, 2H), 1.71-1.84 (m, 6H), 1.54-1.61 (m,2H).

The compounds in examples 10-12 were prepared analogously as describedabove.

Examples 103-(6-Bromopyridin-3-yloxy)-N-(5-hydroxyadamantan-2-yl)benzamide

Example 114-Dimethylamino-N-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)benzamide

Example 124-Dimethylamino-N-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)benzamide

Pharmacological Methods11βHSD1 Enzyme AssayMaterials

³H-cortisone and anti-rabbit Ig coated scintillation proximity assay(SPA) beads were purchased from Amersham Pharmacia Biotech, β-NADPH wasfrom Sigma and rabbit anti-cortisol antibodies were from Fitzgerald. Anextract of yeast transformed with h-11βHSD1 (Hult et al., FEBS Lett,441, 25 (1998)) was used as the source of enzyme. The test compoundswere dissolved in DMSO (10 mM). All dilutions were performed in a buffercontaining 50 mM TRIS-HCl (Sigma Chemical Co), 4 mM EDTA (Sigma ChemicalCo), 0.1% BSA (Sigma Chemical Co), 0.01% Tween-20 (Sigma Chemical Co)and 0.005% bacitracin (Novo Nordisk A/S), pH=7.4. Optiplate 96 wellsplates were supplied by Packard. The amount of ³H-cortisol bound to theSPA beads was measured on TopCount NXT, Packard.

Methods

h-11βHSD1, 120 nM ³H-cortisone, 4 mM β-NADPH, antibody (1:200), serialdilutions of test compound and SPA particles (2 mg/well) were added tothe wells. The reaction was initiated by mixing the different componentsand was allowed to proceed under shaking for 60 min at 30° C. Thereaction was stopped be the addition of 10 fold excess of a stoppingbuffer containing 500 μM carbenoxolone and 1 μM cortisone. Data wasanalysed using GraphPad Prism software.

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications, and substitutions can bemade therein without departing from the spirit and scope of the presentinvention. For example, effective dosages other than the preferreddosages as set forth herein may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated. Likewise,the specific pharmacological responses observed may vary according toand depending on the particular active compound selected or whetherthere are present pharmaceutical carriers, as well as the type offormulation and mode of administration employed, and such expectedvariations or differences in the results are contemplated in accordancewith the objects and practices of the present invention. Accordingly,the invention is not to be limited as by the appended claims.

The features disclosed in the foregoing description and/or in the claimsmay both separately and in any combination thereof be material forrealising the invention in diverse forms thereof.

Preferred Features of the Invention:

1. A compound of the general formula (I):

wherein R¹ is selected from the group consisting of hydrogen, methyl,ethyl, isopropyl and cyclopropyl and R² is selected from the groupconsisting of a monovalent radical having one of the following formulae,wherein the symbol * denotes the point of attachment:

or R¹ and R² together with the nitrogen to which they are attached isselected from the group consisting of one of the following formulaewherein the symbol * denotes the point of attachment:

Q is selected is selected from the group consisting of hydroxy, carboxy,—S(═O)₂R⁶, and S(═O)₂NH₂;P is selected from the group consisting of —S(═O)₂R⁶, carboxy and—S(═O)₂NH₂,R⁶ is selected from the group consisting of C₁-C₄alkyl, phenyl, pyridineand C₃-C₁₀cycloalkyl, wherein said C₁-C₄alkyl, phenyl, pyridine andC₃-C₁₀cycloalkyl are optionally substituted with one or twoindependently selected R⁷;R⁷ is selected from the group consisting of hydrogen, methyl, ethyl,cyclopropyl, —O—CH₃, —O-cyclopropyl, —O-isopropyl, hydroxy, and halogen,wherein said methyl, ethyl, cyclopropyl, —O—CH₃, —O-cyclopropyl and—O-isopropyl is optionally substituted with one substituent selectedfrom the group consisting of hydroxy and halogen;R⁴ is selected from the group consisting of hydrogen, C₁-C₄alkylsubstituted with R¹² and R¹³, —O—(C₁-C₄alkyl) substituted with R¹² andR¹³, trifluoromethyl, —CN, halogen, —S(═O)₂methyl, —S(═O)₂ethyl,—S(═O)₂cyclopropyl, —S(═O)₂NR¹⁰R¹¹ and —C(═O)NR¹⁰R¹¹;R⁹⁵ is selected from the group consisting of C₁-C₆alkyl, phenyl,pyridine, pyrimidine, cyclopropyl, cyclobutyl and cyclohexyl, whereinsaid C₁-C₆alkyl, phenyl, pyridine, pyrimidine, cyclopropyl, cyclobutyland cyclohexyl are optionally substituted with one or two independentlyselected R⁹⁶;R⁹⁶ is selected from the group consisting of halogen, hydroxy, oxo,trifluoromethyl, C₁-C₆alkyl, and —S(═O)₂methyl;R⁹⁷ is selected from the group consisting of hydrogen and C₁-C₆alkyl;R¹² and R¹³ are each independently selected from the group consisting ofhydrogen, —O—(C₁-C₄alkyl), halogen, carboxy and hydroxy;R⁵ is selected from the group consisting of hydrogen, C₁-C₄alkylsubstituted with R¹⁶, trifluoromethyl, —CN, halogen, C₁-C₄alkylcarbonylsubstituted with R¹⁸, —S(═O)₂R¹⁷, —S(═O)₂NR¹⁴R¹⁵, and —S—R¹⁷;R¹⁰ and R¹¹ are each independently selected from the group consisting ofhydrogen, and C₁-C₄alkyl; or R¹⁰ and R¹¹ together with the nitrogen towhich they are attached form a 4 to 6 membered ring, wherein saidC₁-C₄alkyl and each carbon atom in said 4 to 6 membered ring optionallyis substituted with one or two substituents independently selected fromthe group consisting of hydroxy and halogen;R¹⁴ and R¹⁵ are each independently selected from the group consisting ofhydrogen, and C₁-C₄alkyl; or R¹⁴ and R¹⁵ together with the nitrogen towhich they are attached form a 4 to 6 membered ring, wherein saidC₁-C₄alkyl and each carbon atom in said 4 to 6 membered ring optionallyis substituted with one or two substituents independently selected fromthe group consisting of hydroxy and halogen;R¹⁶ and R¹⁸ are each independently selected from the group consisting ofhydrogen, —O-methyl, methyl, cyclopropyl, halogen, —S(═O)₂-methyl,—S(═O)₂-ethyl, —C(═O)NH₂, —C(═O)N—CH₃CH₃, carboxy, and hydroxy;R¹⁷ is selected from the group consisting of hydrogen and C₁-C₆alkyl,wherein said C₁-C₆alkyl is optionally substituted with one or twosubstituents selected from the group consisting of hydroxy and halogen;Y is selected from the group consisting of —X¹—X²—X³—R³, —X¹⁰,—CR⁷²R⁷³—O—CR⁷⁰R⁷¹—R³, —CR⁷²R⁷³—S—CR⁷⁰R⁷¹—R³,—CR⁷²R⁷³—S(═O)₂—CR⁷⁰R⁷¹—R³, —CR⁷²R⁷³—NR²⁵—S(═O)₂—R³,—CR⁷²R⁷³—CR⁷⁰R⁷¹—S(═O)₂—R³, —CR⁷²R⁷³—CR⁷⁰R⁷¹—O—R³,—CR⁷²R⁷³—CR⁷⁰R⁷¹—S—R³, —CR⁷²R⁷³—CR⁷⁰R⁷¹—NR²⁵—R³, —O—CR⁴⁴R⁴⁵—S(═O)₂—R³,—CR⁷²R⁷³—O—R³, —CR⁷²R⁷³—S—R³, —CR⁷²R⁷³—S(═O)₂—R³, —CR⁷²R⁷³—NR²⁵—R³,—CR⁷²R⁷³—S(═O)₂—R³, —O—R¹⁰³, —O—CR⁴⁴R⁴⁵—R¹⁰³, —CR⁷²R⁷³—CR⁴⁴R⁴⁵—R¹⁰³,—O—CR⁴⁴R⁴⁵—CR⁷⁰R⁷¹—R¹⁰³, —CR⁷²R⁷³—CR⁴⁴R⁴⁵—CR⁷⁰R⁷¹—R¹⁰³, and —CH₂—R¹⁰³;X¹ is selected from the group consisting of —S—, —S(═O)—, and —S(═O)₂—;X² is absent or is selected from the group consisting of —O—, —CR⁴⁴R⁴⁵—,—S—, —S(═O)—, —S(═O)₂— and —NR²⁵—;X³ is absent or is selected from the group consisting of —O—, —CR⁷⁰R⁷¹—,—S—, —S(═O)—, —S(═O)₂—, and —NR¹²⁵—;X¹⁰ is selected from the group consisting of C₃-C₁₀cycloalkylsubstituted with R¹⁹ and phenyl substituted with R²²;each R¹⁹ is independently selected from the group consisting of —CN,—C(═O)R⁴⁶, —CH(OH)—R⁴⁷, —(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—C═C—R⁵¹R⁵²,—(CR⁴⁴R⁴⁵)_(m)—C≡C—R⁵³, —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀cycloalkyl substituted withR⁵⁵, and —(CR⁴⁴R⁴⁵)_(m)-aryl substituted with R⁵⁶ and R⁵⁷.each R²² is independently selected from the group consisting of halogen,—CN, hydroxy, —C(═O)OH, —C(═O)R⁴⁶, —CH(OH)—R⁴⁷, hydroxy,—(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)R⁴⁶,—(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—C═C—R⁵¹R⁵², —(CR⁴⁴R⁴⁵)_(m)—C≡C—R⁵³,—(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀heterocyclyl substituted with R⁵⁴,—(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀cycloalkyl substituted with R⁵⁵,—(CR⁴⁴R⁴⁵)_(m)-aryl substituted with R⁵⁶ and R⁵⁷ and—(CR⁴⁴R⁴⁵)_(m)-heteroaryl substituted with R⁵⁶ and R⁵⁷;R²⁴ is selected from the group consisting of —C(═O)—R²⁶, —S(═O)₂—R²⁷,heteroaryl substituted with R²⁸, and aryl substituted with R²⁹;R²⁵ is selected from the group consisting of hydrogen, methyl, ethyl,isobutyl, isopropyl and cyclopropyl;R¹²⁵ is selected from the group consisting of hydrogen, methyl, ethyl,isobutyl, isopropyl and cyclopropyl;R³ is selected from the group consisting of C₃-C₁₀heterocyclylsubstituted with R³⁰ and R³¹, C₃-C₁₀cycloalkyl substituted with R⁹⁰ andR⁹¹, aryl substituted with R³⁰ and R³¹, heteroaryl substituted with R⁹⁰and R⁹¹, —C(═O)R³², —CH(OH)—R³³, —(CR⁴⁴R⁴⁵)_(n)—C(═O)—NR³⁴R³⁵,—(CR⁴⁴R⁴⁵)_(n)—NR³⁶C(═O)R³⁷, —(CR⁴⁴R⁴⁵)_(n)—OR³⁸, —(CR⁴⁴R⁴⁵)_(n)—SR³⁸,—(CR⁴⁴R⁴⁵)_(n)—S(═O)₂R³⁹, —(CR⁴⁴R⁴⁵)_(n)—S(═O)₂NR³⁴R³⁵,—(CR⁴⁴R⁴⁵)_(n)—NR³⁴S(═O)₂—R⁴⁰, —(CR⁴⁴R⁴⁵)_(n)—NR³⁴R³⁵,—(CR⁴⁴R⁴⁵)_(n)—NR³⁴C(═O)—NR³⁴R³⁵, —(CR⁴⁴R⁴⁵)_(n)—C═C—R⁴¹R⁴², and—(CR⁴⁴R⁴⁵)_(n)—C≡C—R⁴³,n is selected from the group consisting of 0, 1 and 2;R⁴⁴ and R⁴⁵ are each independently selected from the group consistinghydrogen, halogen, C₁-C₆alkyl and C₃-C₁₀cycloalkyl, wherein saidC₁-C₆alkyl and C₃-C₁₀cycloalkyl are optionally substituted with one ortwo substituents selected independently from the group consistinghalogen, hydroxy and oxo; or R⁴⁴ and R⁴⁵ together with the carbon atomto which they are attached form a cyclopropyl or cyclobutyl ring,wherein said ring are optionally substituted with hydroxy or halogen;R⁷⁰ and R⁷¹ are each independently selected from the group consistinghydrogen, halogen, C₁-C₆alkyl and C₃-C₁₀cycloalkyl, wherein saidC₁-C₆alkyl and C₃-C₁₀cycloalkyl are optionally substituted with one ortwo substituents selected independently from the group consistinghalogen, hydroxy and oxo; or R⁴⁴ and R⁴⁵ together with the carbon atomto which they are attached form a cyclopropyl or cyclobutyl ring,wherein said ring are optionally substituted with hydroxy or halogen;R⁷² and R⁷³ are each independently selected from the group consistinghydrogen, halogen, C₁-C₆alkyl and C₃-C₁₀cycloalkyl, wherein saidC₁-C₆alkyl and C₃-C₁₀cycloalkyl are optionally substituted with one ortwo substituents selected independently from the group consistinghalogen, hydroxy and oxo; or R⁴⁴ and R⁴⁵ together with the carbon atomto which they are attached form a cyclopropyl or cyclobutyl ring,wherein said ring are optionally substituted with hydroxy or halogen;R³⁰, R³¹, R⁴² and R⁴³ are each independently selected from the groupconsisting of hydrogen, halogen, —CN, —C(═O)OH, —C(═O)R⁴⁶, —CH(OH)—R⁴⁷,trifluoromethyl, hydroxy, —(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)R⁴⁶, —(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹,—(CR⁴⁴—R⁴⁵)_(m)—S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—C═CR⁵¹R⁵²,—(CR⁴⁴R⁴⁵)_(m)—C≡C—R⁵³, —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀heterocyclyl substitutedwith R⁵⁴, —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀cycloalkyl substituted with R⁵⁵,—(CR⁴⁴R⁴⁵)_(m)-aryl substituted with R⁵⁶ and R⁵⁷ and—(CR⁴⁴R⁴⁵)_(m)-heteroaryl substituted with R⁵⁶ and R⁵⁷;R⁹⁰ and R⁹¹ are each independently selected from the group consisting ofhydrogen, halogen, ═O, —CN, —C(═O)OH, —C(═O)R⁴⁶, —CH(OH)—R⁴⁷, hydroxy,trifluoromethyl, —(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)R⁴⁶, —(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—C═CR⁵¹R⁵²,—(CR⁴⁴R⁴⁵)_(m)—C≡C—R⁵³, —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀heterocyclyl substitutedwith R⁵⁴, —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀cycloalkyl substituted with R⁵⁵,—(CR⁴⁴R⁴⁵)_(m)-aryl substituted with R⁵⁶ and R⁵⁷ and—(CR⁴⁴R⁴⁵)_(m)-heteroaryl substituted with R⁵⁶ and R⁵⁷;m is 0 or 1;R³², R³³, R³⁷, R³⁸, R³⁹, R⁴⁰ and R⁴¹ are each independently selectedfrom the group consisting of hydrogen, C₁-C₆alkyl, C₃-C₁₀heterocyclyl,C₃-C₁₀cycloalkyl, aryl and heteroaryl, wherein said C₁-C₆alkyl,C₃-C₁₀heterocyclyl, C₃-C₁₀cycloalkyl, aryl and heteroaryl are optionallysubstituted with one, two or three independently selected R⁵⁸;R³⁴, R³⁵, and R³⁶ are each independently selected from the groupconsisting of hydrogen, C₁-C₆alkyl, C₃-C₁₀cycloalkyl and heteroaryl,wherein said C₁-C₆alkyl, C₃-C₁₀cycloalkyl and heteroaryl are optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of halogen, methyl, ethyl and hydroxy; or R³⁴and R³⁵ together with the nitrogen to which they are attached form a 4to 6 membered ring, wherein said 4 to 6 membered ring optionally issubstituted with one or two substituents independently selected from thegroup consisting of hydroxy or halogen;R²⁶, R²⁷, R⁴⁶, R⁴⁷, R⁴⁹, R⁵⁰, R⁵¹, R⁵² and R⁵³ are each independentlyselected from the group consisting of hydrogen, C₁-C₆alkyl, heteroaryland C₃-C₁₀cycloalkyl, wherein said C₁-C₆alkyl, heteroaryl andC₃-C₁₀cycloalkyl are optionally substituted with one, two or threesubstituents independently selected from the group consisting ofhalogen, methyl, ethyl, methoxy, ethoxy, —OCH₂CH₂OH, carboxy andhydroxy;R⁵⁴, R⁵⁵, R⁵⁶ and R⁵⁷ are each independently selected from the groupconsisting of hydrogen, halogen, —CN, trifluoromethyl, —OCH₂CH₂OH,hydroxyl, C₁-C₆alkyl, heteroaryl and C₃-C₁₀cycloalkyl, wherein saidC₁-C₆alkyl, heteroaryl and C₃-C₁₀cycloalkyl are optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of halogen, methyl, ethyl, methoxy, ethoxy, —OCH₂CH₂OH,carboxy and hydroxy;R⁴⁸ and R⁴⁹ are each independently selected from the group consisting ofhydrogen, C₁-C₆alkyl, tetrahydropyrane, cyclohexyl and cyclopentyl,wherein said C₁-C₆alkyl, tetrahydropyrane, cyclohexyl and cyclopentylare optionally substituted with one or two substituents independentlyselected from the group consisting of halogen and hydroxy; or R⁴⁸ andR⁴⁹ together with the nitrogen to which they are attached form a 4 to 6membered ring, wherein said 4 to 6 membered ring optionally issubstituted with one or two substituents independently selected from thegroup consisting of hydroxy and halogen;R⁵⁸ are each independently selected from the group consisting ofhalogen, —CN, hydroxy, oxo, —C(═O)OH, —S(═O)₂R⁵⁹, —S—NR⁶⁰R⁶¹,S(═O)₂NR⁶⁰R⁶¹, cyclopropyl, C₁-C₆alkyl, —C(═O)NR⁶⁰R⁶¹,—NR⁶⁰C(═O)NR⁶¹R⁶⁰, —NR⁶⁰S(═O)₂R⁵⁹ and —NC(═O)R⁵⁹;R⁵⁹ is selected from the group consisting of hydrogen, C₁-C₆alkyl,C₃-C₁₀cycloalkyl, aryl and heteroaryl, wherein said C₁-C₆alkyl,C₃-C₁₀cycloalkyl, aryl and heteroaryl are optionally substituted withone, two or three substituents independently selected from the groupconsisting of halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl,—CN and hydroxy;R⁶⁰ and R⁶¹ are each independently selected from the group consisting ofhydrogen, C₁-C₆alkyl, C₃-C₁₀heterocyclyl, C₃-C₁₀cycloalkyl andheteroaryl, wherein said C₁-C₆alkyl, C₃-C₁₀heterocyclyl,C₃-C₁₀cycloalkyl and heteroaryl are optionally substituted with one ortwo substituents independently selected from the group consisting ofhalogen and hydroxy; or R⁶⁰ and R⁶¹ together with the nitrogen to whichthey are attached form a 4 to 6 membered ring, wherein said 4 to 6membered ring optionally is substituted with one or two substituentsindependently selected from the group consisting of hydroxy and halogen;R¹⁰³ is selected from the group consisting of C₃-C₁₀heterocyclylsubstituted with two substituents independently selected from the groupconsisting of R⁶² and R⁶³, C₃-C₁₀cycloalkyl substituted with R³⁰ andR³¹, aryl substituted with R³⁰ and R³¹, heteroaryl substituted with twosubstituents independently selected from the group consisting of R⁶² andR⁶³, —C(═O)R⁹³, —CH(OH)—R³³, —C(═O)—NR⁹⁴R⁹⁵, —NR³⁶C(═O)R³⁷, —OR³⁸,—SR³⁸, —S(═O)₂R³⁹, —S(═O)₂NR³⁴R³⁵, —NR³⁴S(═O)₂—R⁴⁰, —NR²⁴R²⁵—,—NR³⁴C(═O)—NR³⁴R³⁵, —C═C substituted with R⁴¹ and R⁴², W and —C≡Csubstituted with R⁴³;W is selected from the group consisting of pyrrolidinone,tetrahydropyrane, 1,4-dioxane, aziridinone, azetidinone, piperidinone,thiazole, imidazole, tetrahydrofurane and oxepane;R⁹³ is selected from the group consisting of hydrogen,C₃-C₁₀heterocyclyl, C₃-C₁₀cycloalkyl, aryl and heteroaryl, wherein saidC₃-C₁₀heterocyclyl, C₃-C₁₀cycloalkyl, aryl and heteroaryl are optionallysubstituted with one, two or three independently selected R⁵⁸;R⁹⁴ and R⁹⁵ are each independently selected from the group consisting ofhydrogen, C₃-C₁₀cycloalkyl and heteroaryl, wherein said C₃-C₁₀cycloalkyland heteroaryl are optionally substituted with one, two or threesubstituents independently selected from the group consisting ofhalogen, methyl, ethyl and hydroxy; or R⁹⁴ and R⁹⁵ together with thenitrogen to which they are attached form a 4 to 6 membered ring, whereinsaid 4 to 6 membered ring optionally is substituted with one or twosubstituents independently selected from the group consisting of hydroxyor halogen;R⁶² is selected from the group consisting of halogen, —C(═O)OH,—CH(OH)—R⁴⁷, —C(═O)—NR⁴⁸R⁴⁹, —NR⁴⁸C(═O)R⁴⁶, —SR⁴⁹, —S(═O)₂R⁵⁰,—S(═O)₂NR⁴⁸R⁴⁹, —NR⁴⁸S(═O)₂R⁵⁰, —NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, —C═C—R⁵¹R⁵²,—C≡C—R⁵³, CH₂CH₂OH, —CH₂CH₂OH, C₃-C₁₀heterocyclyl substituted with R⁵⁴,C₃-C₁₀cycloalkyl substituted with R⁵⁵, aryl substituted with R⁵⁶ and R⁵⁷and heteroaryl substituted with R⁵⁶ and R⁵⁷;R⁶³ is selected from the group consisting of hydrogen, ═O, halogen,hydroxy, trifluoromethyl, —CN, oxo, —C(═O)OH, —S(═O)₂R⁵⁹,—S(═O)₂NR⁶⁰R⁶¹, —S(═O)NR⁶⁰R⁶¹ cyclopropyl, —OR⁵⁹, —SR⁵⁹, —C₁-C₆alkyl,—C(═O)NR⁶⁰R⁶¹, —NR⁶⁰C(═O)NR⁶¹R⁶⁰; —NR⁶⁰S(═O)₂R⁵⁹, and —N(C═O)R⁵⁹;a salt thereof with a pharmaceutically acceptable acid or base, or anyoptical isomer or mixture of optical isomers, including a racemicmixture, or any tautomeric forms.

2. The compound according to clause 1, wherein Y is —X¹—X²—X³—R³.

3. The compound according to clause 2, wherein X¹ is selected from thegroup consisting of —S— and —S(═O)₂—.

4. The compound according to clause 3, wherein X¹ is —S(═O)₂—.

5. The compound according to any one of clauses 2-4, wherein X² isabsent or is selected from the group consisting of —CR⁴⁴R⁴⁵— and —NR²⁵—.

6. The compound according to clause 5, wherein X² is absent or is—CR⁴⁴R⁴⁵.

7. The compound according to any one of clauses 2-6, wherein X³ isabsent or is —CR⁷⁰R⁷¹—.

8. The compound according to any one of clauses 2-7, wherein—X¹—X²—X³—R³ is selected from the group consisting of —S—R³, —S(═O)₂—R³,—S(═O)₂—NR²⁵R³, —(═O)₂—CR⁴⁴R⁴⁵—R³.

9. The compound according to clause 8, wherein —X¹—X²—X³—R³ is selectedfrom the group consisting of —S—R³, —S(═O)₂—R³.

10. The compound according to clause 8, wherein —X¹—X²—X³—R³ is selectedfrom the group consisting of —S(═O)₂—NR²⁵R³, —S(═O)₂—CR⁴⁴R⁴⁵—R³.

11. The compound according to clause 1, wherein Y is selected from thegroup consisting of —CR⁷²R⁷³—O—CR⁷⁰R⁷¹—R³, —CR⁷²R⁷³—S—CR⁷⁰R⁷¹—R³,—CR⁷²R⁷³—S(═O)₂—CR⁷⁰R⁷¹—R³, —CR⁷²R⁷³—NR²⁵—S(═O)₂—R³,—CR⁷²R⁷³—CR⁷⁰R⁷¹—S(═O)₂—R³, —CR⁷²R⁷³—CR⁷⁰R⁷¹—O—R³,—CR⁷²R⁷³—CR⁷⁰R⁷¹—S—R³, —CR⁷²R⁷³—CR⁷⁰R⁷¹—NR²⁵—R³, —O—CR⁴⁴R⁴⁵—S(═O)₂—R³,—CR⁷²R⁷³—O—R³, —CR⁷²R⁷³—S—R³, —CR⁷²R⁷³—S(═O)₂—R³, —CR⁷²R⁷³—NR²⁵—R³,—CR⁷²R⁷³—S(═O)₂—R³, —O—R¹⁰³, —O—CR⁴⁴R⁴⁵—R¹⁰³, —CR⁷²R⁷³—CR⁴⁴R⁴⁵—R¹⁰³,—O—CR⁴⁴R⁴⁵—CR⁷⁰R⁷¹—R¹⁰³, —CR⁷²R⁷³—CR⁴⁴R⁴⁵—CR⁷⁰R⁷¹—R¹⁰³, and—CR⁷²R⁷³—R¹⁰³.

12. The compound according to clause 11, wherein Y is selected from thegroup consisting of —CR⁷²R⁷³—O—CR⁷⁰R⁷¹—R³, —CR⁷²R⁷³—S—CR⁷⁰R⁷¹—R³,—CR⁷²R⁷³—S(═O)₂—CR⁷⁰R⁷¹—R³, —CR⁷²R⁷³—NR²⁵—S(═O)₂—R³,—CR⁷²R⁷³—CR⁷⁰R⁷¹—S(═O)₂—R³, —CR⁷²R⁷³—CR⁷⁰R⁷¹—O—R³ and—CR⁷²R⁷³—CR⁷⁰R⁷¹—NR²⁵—R³.

13. The compound according to clause 12, wherein Y is selected from thegroup consisting of —CR⁷²R⁷³—O—CR⁷⁰R⁷¹—R³, —CR⁷²R⁷³—S—CR⁷⁰R⁷¹—R³,—CR⁷²R⁷³—CR⁷⁰R⁷¹—O—R³ and —CR⁷²R⁷³—CR⁷⁰R⁷¹—NR²⁵—R³.

14. The compound according to clause 11, wherein Y is selected from thegroup consisting of —CR⁷²R⁷³—S(═O)₂—CR⁷⁰R⁷¹—R³,—CR⁷²R⁷³—CR⁷⁰R⁷¹—S(═O)₂—R³ and —CR⁷²R⁷³—NR²⁵—S(═O)₂—R³.

15. The compound according to clause 11, wherein Y is selected from thegroup consisting of —CR⁷²R⁷³—O—CR⁷⁰R⁷¹—R³, —CR⁷²R⁷³—CR⁷⁰R⁷¹—O—R³ and—CR⁷²R⁷³—CR⁷⁰R⁷¹—NR²⁵—R³.

16. The compound according to clause 1, wherein Y is selected from thegroup consisting of C₃-C₁₀cycloalkyl substituted with R¹⁹ and phenylsubstituted with R²².

17. The compound according to clause 16, wherein Y is C₃-C₁₀cycloalkylsubstituted with R¹⁹,

18. The compound according to clause 16, wherein Y is phenyl substitutedwith R²².

19. The compound according to any one of clauses 1-15, wherein R³ isselected from the group consisting of C₃-C₁₀heterocyclyl substitutedwith R³⁰ and R³¹, C₃-C₁₀cycloalkyl substituted with R⁹⁰ and R⁹¹, arylsubstituted with R³⁰ and R³¹, heteroaryl substituted with R⁹⁰ and R⁹¹.

20. The compound according to any one of clauses 1-15, wherein R³ isselected from the group consisting of —C(═O)R³², —CH(OH)—R³³,—(CR⁴⁴R⁴⁵)_(n)—C(═O)—NR³⁴R³⁵, —(CR⁴⁴R⁴⁵)_(n)—NR³⁶C(═O)R³⁷,—(CR⁴⁴R⁴⁵)_(n)—OR³⁸, —(CR⁴⁴R⁴⁵)_(n)—SR³⁸, —(CR⁴⁴R⁴⁵)_(n)—S(═O)₂R³⁹,—(CR⁴⁴R⁴⁵)_(n)—S(═O)₂NR³⁴R³⁵, —(CR⁴⁴R⁴⁵)_(n)—NR³⁴S(═O)₂—R⁴⁰,—(CR⁴⁴R⁴⁵)_(n)—NR³⁴R³⁵, —(CR⁴⁴R⁴⁵)_(n)—NR³⁴C(═O)—NR³⁴R³⁵,—(CR⁴⁴R⁴⁵)_(n)—C═C—R⁴¹R⁴² and —(CR⁴⁴R⁴⁵)_(n)—C≡C—R⁴³.

21. The compound according to any one of clauses 1-15, wherein R³ isselected from the group consisting of C₃-C₁₀heterocyclyl substitutedwith R³⁰, C₃-C₁₀cycloalkyl substituted with R⁹⁰, aryl substituted withR³⁰, heteroaryl substituted with R⁹⁰, —(CR⁴⁴R⁴⁵)_(n)—C(═O)—NR³⁴R³⁵,—(CR⁴⁴R⁴⁵)_(n)—NR³⁶C(═O)R³⁷, —(CR⁴⁴R⁴⁵)_(n)—OR³⁸,—(CR⁴⁴R⁴⁵)_(n)—S(═O)₂R³⁹, —(CR⁴⁴R⁴⁵)_(n)—S(═O)₂NR³⁴R³⁵,—(CR⁴⁴R⁴⁵)_(n)—NR³⁴S(═O)₂—R⁴⁰, —(CR⁴⁴R⁴⁵)_(n)—NR³⁴C(═O)—NR³⁴R³⁵,—(CR⁴⁴R⁴⁵)_(n)—C═CR⁴¹R⁴² and —(CR⁴⁴R⁴⁵)_(n)—C≡C—R⁴³.

22. The compound according to any one of clauses 1-15, wherein R³ isselected from the group consisting of C₃-C₁₀heterocyclyl substitutedwith R³⁰, C₃-C₁₀cycloalkyl substituted with R⁹⁰, aryl substituted withR³⁰; heteroaryl substituted with R⁹⁰, —C(═O)—NR³⁴R³⁵, —NR³⁶C(═O)R³⁷,—OR³⁸, —S(═O)₂R³⁹, —S(═O)₂NR³⁴R³⁵, —NR³⁴S(═O)₂—R⁴⁰, —NR³⁴C(═O)—NR³⁴R³⁵,—C═CR⁴¹R⁴² and —C≡C—R⁴³.

23. The compound according to any one of clauses 1-15, wherein R³ isselected from the group consisting of C₃-C₁₀heterocyclyl substitutedwith R³⁰, C₃-C₁₀cycloalkyl substituted with R⁹⁰, heteroaryl substitutedwith R³⁰, —C(═O)—NR³⁴R³⁵, —NR³⁶C(═O)R³⁷, —OR³⁸, —S(═O)₂R³⁹,—S(═O)₂NR³⁴R³⁵, —NR³⁴S(═O)₂—R⁴⁰, —NR³⁴C(═O)—NR³⁴R³⁵, —C═CR⁴¹R⁴² and—C≡C—R⁴³.

24. The compound according to any one of clauses 1-15, wherein R³ isselected from the group consisting of piperidine substituted with R³⁰,pyrrolidine substituted with R³⁰, morpholine substituted with R³⁰,tetrahydropyranyl substituted with R³⁰, cyclohexyl substituted with R³⁰,cyclopropyl substituted with R³⁰, cyclobutyl substituted with R³⁰,cyclopentyl substituted with R³⁰, phenyl substituted with R³⁰;pyridazinyl substituted with R³⁰, pyrazinyl substituted with R³⁰,pyridine substituted with R³⁰, imidazolyl substituted with R³⁰,pyrazolyl substituted with R³⁰ and pyrimidinyl substituted with R³⁰,isoxazolyl substituted with R³⁰, pyridinyl substituted with R³⁰,—C(═O)—NR³⁴R³⁵, —NR³⁶C(═O)R³⁷, —OR³⁸, —S(═O)₂R³⁹, —S(═O)₂NR³⁴R³⁵,—NR³⁴S(═O)₂—R⁴⁰, —NR³⁴C(═O)—NR³⁴R³⁵ and —C≡C—R⁴³.

25. The compound according to any one clauses 1-15, wherein R³ isselected from the group consisting of piperidine substituted with R³⁰,pyrrolidine substituted with R³⁰, morpholine substituted with R³⁰,tetrahydropyranyl substituted with R³⁰, cyclohexyl substituted with R³⁰,cyclopropyl substituted with R³⁰, cyclobutyl substituted with R³⁰,cyclopentyl substituted with R³⁰, phenyl substituted with R³⁰;pyridazinyl substituted with R³⁰, pyrazinyl substituted with R³⁰,pyridine substituted with R³⁰, imidazolyl substituted with R³⁰,pyrazolyl substituted with R³⁰ and pyrimidinyl substituted with R³⁰,isoxazolyl substituted with R³⁰, pyridinyl substituted with R³⁰.

26. The compound according to any one of clauses 1-15, wherein R³ isselected from the group consisting of —NR³⁶C(═O)R³⁷, —NR³⁴S(═O)₂—R⁴⁰ and—NR³⁴C(═O)—NR³⁴R³⁵.

27. The compound according to any one of clauses 1-15, wherein R³ isselected from the group consisting of —C(═O)—NR³⁴R³⁵, —OR³⁸, —S(═O)₂R³⁹,—S(═O)₂NR³⁴R³⁵ and —C_═C—R⁴³.

28. The compound according to any one of clauses 1-15, wherein n isselected from the group consisting of 0 or 1.

29. The compound according to clause 28, wherein n is 0.

30. The compound according to clause 11, wherein R¹⁰³ is selected fromthe group consisting of —C(═O)R⁹³, —CH(OH)—R³³, —C(═O)—NR⁹⁴R⁹⁵,—NR³⁶C(═O)R³⁷, —OR³⁸, —SR³⁸, —S(═O)₂R³⁹, —S(═O)₂NR³⁴R³⁵,—NR³⁴S(═O)₂—R⁴⁰, —NR²⁴R²⁵—, —NR³⁴C(═O)—NR³⁴R³⁵, —C═C substituted withR⁴¹ and R⁴², W and —C≡C substituted with R⁴³.

31. The compound according to clause 11, wherein R¹⁰³ is selected fromthe group consisting of C₃-C₁₀heterocyclyl substituted with twosubstitutions independently selected from the group consisting of R⁶²and R⁶³, C₃-C₁₀cycloalkyl substituted with R³⁰ and R³¹, aryl substitutedwith R³⁰ and R³¹, heteroaryl substituted with two substitutionsindependently selected from the group consisting of R⁶² and R⁶³.

32. The compound according to clause 11, wherein R¹⁰³ is selected fromthe group consisting of C₃-C₁₀heterocyclyl substituted with twosubstitutions independently selected from the group consisting of R⁶²and R⁶³ and heteroaryl substituted with two substitutions independentlyselected from the group consisting of R⁶² and R⁶³.

33. The compound according to clause 11, wherein R¹⁰³ is selected fromthe group consisting of cyclopropyl, cyclobutyl, cyclohexyl andcyclopentyl substituted with R³⁰ and R³¹ and phenyl substituted with R³⁰and R³¹, tetrahydropyranyl, piperidinyl, pyrrolidinyl and morpholinylsubstituted with two substitutions independently selected from the groupconsisting of R⁶² and R⁶³ and imidazolyl, pyrazolyl, isoxazolyl,pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl substituted with twosubstitutions independently selected from the group consisting of R⁶²and R⁶³.

34. The compound according to clause 11, wherein R¹⁰³ is selected fromthe group consisting of tetrahydropyranyl, piperidinyl, pyrrolidinyl andmorpholinyl substituted with two substitutions independently selectedfrom the group consisting of R⁶² and R⁶³ and imidazolyl, pyrazolyl,isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl substitutedwith one or two substitutions independently selected from the groupconsisting of R⁶² and R⁶³.

35. The compound according to any one of clauses 31-34, wherein R¹⁰³comprises at least one R⁶² group.

36. The compound according to clause 11, wherein R¹⁰³ is selected fromthe group consisting of C₃-C₁₀cycloalkyl substituted with R³⁰ and R³¹and aryl substituted with R³⁰ and R³¹;

37. The compound according to clause 11, wherein R¹⁰³ is selected fromthe group consisting of cyclopropyl, cyclobutyl, cyclohexyl, phenyl andcyclopentyl substituted with R³⁰ and R³¹;

38. The compound according to clause 11, wherein R¹⁰³ is selected fromthe group consisting of —C(═O)—NR⁹⁴R⁹⁵, —NR³⁶C(═O)R³⁷, —OR³⁸,—SR³⁸—S(═O)₂R³⁹, —S(═O)₂NR³⁴R³⁵, —NR³⁴S(═O)₂—R⁴⁰, —NR³⁴C(═O)—NR³⁴R³⁵, Wand —C≡C substituted with R⁴³.

39. The compound according to clause 11, wherein R¹⁰³ is selected fromthe group consisting of —C(═O)—NR⁹⁴R⁹⁵, —NR³⁶C(═O)R³⁷, —OR³⁸, S(═O)₂R³⁹,—S(═O)₂NR³⁴R³⁵, —NR³⁴S(═O)₂—R⁴⁰, —NR³⁴C(═O)—NR³⁴R³⁵ and W.

40. The compound according to clause 11, wherein R¹⁰³ is selected fromthe group consisting of —NR³⁶C(═O)R³⁷, —NR³⁴S(═O)₂—R⁴⁰ and—NR³⁴C(═O)—NR³⁴R³⁵.

41. The compound according to clause 11, wherein R¹⁰³ is selected fromthe group consisting of —C(═O)—NR⁹⁴R⁹⁵, —OR³⁸, —S(═O)₂R³⁹,—S(═O)₂NR³⁴R³⁵ and W.

42. The compound according to clause 11, wherein R¹⁰³ is W selected fromthe group consisting of pyrrolidinone, tetrahydropyrane, 1,4-dioxane,piperidinone, thiazole, imidazole and tetrahydrofurane.

43. The compound according to clause 11, wherein R¹⁰³ is W selected fromthe group consisting of pyrrolidinone, tetrahydropyrane, piperidinoneand imidazole.

44. The compound according to any one clauses 1-43, wherein R¹ isselected from the group consisting of hydrogen, methyl, ethyl, isopropyland cyclopropyl and R² is selected from the group consisting of amonovalent radical having one of the following formulae, wherein thesymbol * denotes the point of attachment:

45. The compound according to clause 44, wherein R¹ is selected from thegroup consisting of hydrogen and methyl.

46. The compound according to clause 44, wherein R¹ is hydrogen.

47. The compound according to clause 44, wherein R¹ is methyl.

48. The compound according to any one of clauses 44-47, wherein R² isselected from the group consisting of:

49. The compound according to clause 48, wherein R² is selected from thegroup consisting of:

50. The compound according to clause 48, wherein R² is

51. The compound according to clause 48, wherein R² is

52. The compound according to clause 48, wherein R² is

53. The compound according to clause 48, wherein R² is

54. The compound according to clause 48, wherein R² is

55. The compound according to clause 48, wherein R² is

56. The compound according to any one of clauses 1-43, wherein R¹ and R²together with the nitrogen to which they are attached is selected fromthe group consisting of:

57. The compound according to clause 56, wherein R¹ and R² together withthe nitrogen to which they are attached is

58. The compound according to any one any one of clauses 44-51 and53-57, wherein Q is a hydroxyl group.

59. The compound according to any one of any one of clauses 44-51 and53-57, wherein Q is a carboxy group.

60. The compound according to any one of clauses 44-51 and 53-57,wherein Q is a —S(═O)₂R⁶ group.

61. The compound according to any one of clauses 44-51 and 53-57,wherein Q is selected is a —S(═O)₂NH₂ group.

62. The compound according to any one of clauses 44-52 wherein P is a—S(═O)₂R⁶ group.

63. The compound according to any one of clauses 44-52, wherein P is acarboxy group.

64. The compound according to any one of clauses 44-52, wherein P is a—S(═O)₂NH₂ group.

65. The compound according to clause 60 or 62, wherein R⁶ is selectedfrom the group consisting of methyl, isopropyl, ethyl, phenyl, pyridine,cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl, wherein saidmethyl, isopropyl, ethyl, phenyl, pyridine, cyclopropyl, cyclobutyl,cyclohexyl and cyclopentyl are optionally substituted with one or twoindependently selected R⁷.

66. The compound according to clause 60 or 62, wherein R⁶ is selectedfrom the group consisting of methyl, ethyl, isopropyl, phenyl, pyridine,cyclopropyl and cyclohexyl, wherein said methyl, isopropyl, phenyl,pyridine, cyclopropyl and cyclohexyl are optionally substituted with R⁷.

67. The compound according to clauses 65 or 66, wherein R⁷ is selectedfrom the group consisting of hydrogen, methyl, cyclopropyl, —O—CH₃,—O-cyclopropyl, —O-isopropyl, hydroxy, fluoride and chloride, whereinsaid methyl, ethyl, cyclopropyl, —O—CH₃, —O-isopropyl and —O-cyclopropylis optionally substituted with one substituent selected from the groupconsisting of hydroxy and halogen.

68. The compound according to clause 65 or 66, wherein R⁷ is selectedfrom the group consisting of hydrogen, methyl, cyclopropyl,—O-cyclopropyl, —O-isopropyl, hydroxy, fluoride and chloride, whereinsaid ethyl, cyclopropyl and —O-cyclopropyl is optionally substitutedwith one substituent selected from the group consisting of hydroxy andhalogen.

69. The compound according to any one clauses 1-68, wherein R⁴ isselected from the group consisting of hydrogen, methyl, isopropyl,ethyl, —O-methyl, —O-isopropyl, —O-ethyl, wherein said, methyl,isopropyl, ethyl, —O-methyl, —O-isopropyl, —O-ethyl are substituted withR¹² and R¹³, trifluoromethyl, CN, fluorine, chlorine, —S(═O)₂methyl,—S(═O)₂ethyl, —S(═O)₂cyclopropyl, —S(═O)₂NHR¹¹ and —C(═O)NHR¹⁰.

70. The compound according to any one clauses 1-68, wherein R⁴ isselected from the group consisting of hydrogen, methyl, isopropyl,ethyl, —O-methyl, —O-isopropyl, —O-ethyl, wherein said, methyl,isopropyl, ethyl, —O-methyl, —O-isopropyl, —O-ethyl are, substitutedwith R¹², trifluoromethyl, fluorine, chlorine, —S(═O)₂(methyl)₂,—S(═O)₂methyl, —S(═O)₂ethyl, —S(═O)₂cyclopropyl, —S(═O)₂Nmethyl,—S(═O)₂Nisopropyl, —C(═O)Nisopropyl, —C(═O)N(methyl)₂ and —C(═O)Nmethyl.

71. The compound according to any one clause 1-68, wherein R⁴ isselected from the group consisting of hydrogen, methyl, isopropyl,—O-methyl, —O-isopropyl, —O-ethyl, trifluoromethyl, fluorine, chlorine,—S(═O)₂methyl, —S(═O)₂ethyl, —S(═O)₂cyclopropyl, —S(═O)₂Nmethyl,—S(═O)₂Nisopropyl, —C(═O)Nisopropyl and —C(═O)Nmethyl.

72. The compound according to any one of clauses 69-71 wherein R⁴ is inthe ortho position.

73. The compound according to any one of clauses 69-71, wherein R⁴ is inthe meta position.

74. The compound according to any one of clauses 44-48 and 69-73,wherein R⁹⁵ is selected from the group consisting of methyl, isopropyl,ethyl, phenyl, pyridine, pyrimidine, cyclopropyl, cyclobutyl andcyclohexyl, wherein said ethyl, phenyl, pyridine, pyrimidine,cyclopropyl, cyclobutyl and cyclohexyl are optionally substituted withone or two independently selected R⁹⁶.

75. The compound according to any one of clauses 44-48 and 69-73 whereinR⁹⁵ is selected from the group consisting of methyl, isopropyl, phenyl,pyridine, pyrimidine, cyclopropyl and cyclohexyl, wherein said ethyl,phenyl, pyridine, pyrimidine, cyclopropyl and cyclohexyl are optionallysubstituted with one R⁹⁶.

76. The compound according to clauses 74 or 75, wherein R⁹⁶ is selectedfrom the group consisting of fluorine, chlorine, hydroxy, oxo,trifluoromethyl, methyl, isopropyl, ethyl and —S(═O)₂methyl.

77. The compound according clauses 74 or 75, wherein R⁹⁶ is selectedfrom the group consisting of fluorine, chlorine, hydroxy,trifluoromethyl, methyl, isopropyl and —S(═O)₂methyl.

78. The compound according to any one of clauses 44-48 and 69-73,wherein R⁹⁷ is selected from the group consisting of hydrogen, methyl,isopropyl and ethyl.

79. The compound according to any one of clauses 44-48 and 69-73,wherein R⁹⁷ is selected from the group consisting of hydrogen, methyland isopropyl.

80. The compound according to any one of clauses 1-79, wherein R¹² isselected from the group consisting of hydrogen, —O-(methyl, isopropyl,ethyl), fluorine, chlorine, carboxy and hydroxy.

81. The compound according to any one of clauses 1-79, wherein R¹² isselected from the group consisting of hydrogen, —O-methyl, —O-isopropyl,fluorine and hydroxy.

82. The compound according to any one of clauses 1-81, wherein R¹³ isselected from the group consisting of hydrogen, —O-(methyl, isopropyl,ethyl), fluorine, chlorine, carboxy and hydroxy.

83. The compound according to any one of clauses 1-79, wherein R¹³ isselected from the group consisting of hydrogen, —O-methyl, —O-isopropyl,fluorine and hydroxy.

84. The compound according to any one of clauses 1-83, wherein R⁵ isselected from the group consisting of hydrogen, methyl, isopropyl,ethyl, trifluoromethyl, CN, fluorine, chlorine, acetyl, ethyl, carbonyl,—S(═O)₂R¹⁷, S(═O)₂NR¹⁴R¹⁵, S-methyl, S-isopropyl, and S-ethyl; whereinsaid methyl, isopropyl, ethyl are substituted with R¹⁶ and; wherein saidethyl and carbonyl are substituted with R¹⁸.

85. The compound according to any one of clauses 1-83, wherein R⁵ isselected from the group consisting of hydrogen, methyl, isopropyl,ethyl, trifluoromethyl, fluorine, chlorine, acetyl, —S(═O)₂methyl,—S(═O)₂ isopropyl, S(═O)₂NH₂, S(═O)₂N(CH₃)₂, S-methyl, S-isopropyl, andS-ethyl; wherein said methyl, isopropyl, and ethyl are optionallysubstituted with fluorine or hydroxyl.

86. The compound according to any one clauses 1-83, wherein R⁵ isselected from the group consisting of hydrogen, methyl, isopropyl,trifluoromethyl, fluorine, chlorine, acetyl, —S(═O)₂methyl and —S(═O)₂isopropyl.

87. The compound according to any one of clauses 1-86, wherein R¹⁰ andR¹¹ are each independently selected from the group consisting ofhydrogen, and C₁-C₄alkyl.

88. The compound according to any one of clauses 1-86, wherein R¹⁰ andR¹¹ are each independently selected from the group consisting ofhydrogen, methyl, ethyl and isopropyl.

89. The compound according to any one clauses 1-86, wherein R¹⁰ and R¹¹together with the nitrogen to which they are attached form apiperidinyl, pyrrolidinyl and morpholinyl ring, wherein said ringoptionally is substituted with one or two substituents independentlyselected from the group consisting of hydroxy and fluoride.

90. The compound according to any one clauses 1-86, wherein R¹⁰ and R¹¹together with the nitrogen to which they are attached form apiperidinyl, ring, wherein said ring optionally is substituted with oneor two substituents independently selected from the group consisting ofhydroxy and fluoride.

91. The compound according to any one of clauses 1-90, wherein R¹⁴ andR¹⁵ are each independently selected from the group consisting ofhydrogen, and C₁-C₄alkyl.

92. The compound according to any one of clauses 1-90, wherein R¹⁴ andR¹⁵ are each independently selected from the group consisting ofhydrogen, methyl, ethyl and isopropyl.

93. The compound according to any one of clauses 1-90, wherein R¹⁴ andR¹⁵ together with the nitrogen to which they are attached form apiperidinyl, pyrrolidinyl and morpholinyl ring wherein said ringoptionally is substituted with one or two substituents independentlyselected from the group consisting of hydroxy and fluoride.

94. The compound according to any one of clauses 1-90, wherein R¹⁴ andR¹⁵ together with the nitrogen to which they are attached form apiperidinyl ring, wherein said ring optionally is substituted with oneor two substituents independently selected from the group consisting ofhydroxy and fluoride

95. The compound according to any one of clauses 1-94, wherein R¹⁶ isselected from the group consisting of hydrogen —O-methyl, methyl,cyclopropyl, fluorine, chlorine, —S(═O)₂-methyl, —S(═O)₂-ethyl,—C(═O)NH₂, —C(═O)N—CH₃CH₃, carboxy, and hydroxy.

96. The compound according to any one of clauses 1-94, wherein R¹⁶ isselected from the group consisting of hydrogen, methyl, cyclopropyl,fluorine, —S(═O)₂-methyl, —C(═O)N—(CH₃)₂ and hydroxy.

97. The compound according to any one of clauses 1-96, wherein R¹⁸ isselected from the group consisting of hydrogen —O-methyl, methyl,cyclopropyl, fluorine, chlorine, —S(═O)₂-methyl, —S(═O)₂-ethyl,—C(═O)NH₂, —C(═O)N—CH₃CH₃, carboxy, and hydroxy.

98. The compound according to any one of clauses 1-96, wherein R¹⁸ isselected from the group consisting of hydrogen, methyl, cyclopropyl,fluoride, —S(═O)₂-methyl, —C(═O)N—(CH₃)₂ and hydroxy.

99. The compound according to any one clauses 1-98, wherein R¹⁷ isselected from the group consisting of hydrogen, methyl, ethyl andisopropyl, wherein said ethyl and isopropyl is optionally substitutedwith one or two substituents selected from the group consisting ofhydroxyl, fluorine and chlorine.

100. The compound according to any one of clauses 1-98, wherein R¹⁷ isselected from the group consisting of hydrogen, methyl, ethyl andisopropyl, wherein said ethyl is optionally substituted with onesubstituents selected from the group consisting of hydroxy and fluorine.

101. The compound according to any one of clauses 1-100, wherein R¹⁹ isselected from the group consisting of halogen, —CN, —C(═O)R⁴⁶,—CH(OH)—R⁴⁷, —(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—C═C—R⁵¹R⁵²,and —(CR⁴⁴R⁴⁵)_(m)—C≡C≡R⁵³.

102. The compound according to any one of clauses 1-100, wherein R¹⁹ isselected from the group consisting of, —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀cycloalkylsubstituted with R⁵⁵, and —(CR⁴⁴R⁴⁵)_(m)-aryl substituted with R⁵⁶ andR⁵⁷.

103. The compound according to any one of clauses 1-100, wherein R¹⁹ isselected from the group consisting of —CN, —(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹.

104. The compound according to any one of clauses 1-100, wherein R¹⁹ isselected from the group consisting of, —C₃-C₁₀cycloalkyl substitutedwith R⁵⁵, and -phenyl substituted with R⁵⁶.

105. The compound according to any one of clauses 1-100, wherein R¹⁹ isselected from the group consisting of —CN, —C(═O)—NR⁴⁸R⁴⁹,—NR⁴⁸C(═O)R⁴⁶, —OR⁴⁹, —S(═O)₂R⁵⁰, —S(═O)₂NR⁴⁸R⁴⁹, —NR⁴⁸S(═O)₂R⁵⁰,—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹.

106. The compound according to any one of clauses 1-105, wherein R²² isselected from the group consisting of halogen, —CN, hydroxy, —C(═O)OH,—C(═O)R⁴⁶, —CH(OH)—R⁴⁷, hydroxy, —(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)R⁴⁶, —(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰, —(CR⁴⁴—R⁴⁵)_(m)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—C═C—R⁵¹R⁵²,—(CR⁴⁴R⁴⁵)_(m)—C≡C—R⁵³.

107. The compound according to any one of clauses 1-105 wherein R²² isselected from the group consisting of —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀heterocyclylsubstituted with R⁵⁴, —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀cycloalkyl substituted withR⁵⁵, —(CR⁴⁴R⁴⁵)_(m)-aryl substituted with R⁵⁶ and R⁵⁷ and—(CR⁴⁴R⁴⁵)_(m)-heteroaryl substituted with R⁵⁶ and R⁵⁷.

108. The compound according to any one of clauses 1-105, wherein R²² isselected from the group consisting of fluorine, chlorine, —CN, hydroxy,—C(═O)OH, —(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)R⁴⁶,—(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)NR⁴⁸S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹.

109. The compound according to any one of clauses 1-105 wherein R²² isselected from the group consisting of —C₃-C₁₀heterocyclyl substitutedwith R⁵⁴, —C₃-C₁₀cycloalkyl substituted with R⁵⁵, -phenyl substitutedwith R⁵⁶ and -heteroaryl substituted with R⁵⁶.

110. The compound according to any one clauses 1-105, wherein R²² isselected from the group consisting of fluorine, chlorine, —CN, hydroxy,—C(═O)OH, —C(═O)—NR⁴⁸R⁴⁹, —NR⁴⁸C(═O)R⁴⁶, —OR⁴⁹, —S(═O)₂R⁵⁰,—S(═O)₂NR⁴⁸R⁴⁹, —NR⁴⁸S(═O)₂R⁵⁰, —NR⁴⁸C(═O)—NR⁴⁸R⁴⁹.

111. The compound according to any one of clauses 1-105, wherein R²² isselected from the group consisting of tetrahydropyranyl, piperidinyl,pyrrolidinyl and morpholinyl substituted with R⁵⁴, cyclopropyl,cyclobutyl, cyclohexyl and cyclopentyl substituted with R⁵⁵, -phenylsubstituted with R⁵⁶ and imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl,pyrazinyl pyrimidinyl and pyridinyl substituted with R⁵⁶.

112. The compound according to any one of clauses 1-105, wherein R²² isselected from the group consisting of tetrahydropyranyl, piperidinyl andmorpholinyl substituted with R⁵⁴, cyclopropyl, cyclobutyl, cyclohexyland cyclopentyl substituted with R⁵⁵, phenyl substituted with R⁵⁶ andpyridazinyl, pyrazinyl pyrimidinyl and pyridinyl substituted with R⁵⁶.

113. The compound according to any one of clauses 1-105, wherein R²² isselected from the group consisting of C═C—R⁵¹R⁵², —C≡C—R⁵³ and—CH₂CH₂OH.

114. The compound according to any one of clauses 1-113, wherein R²⁴ isselected from the group consisting of —C(═O)—R²⁶, —S(═O)₂—R²⁷,imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyland pyridinyl substituted with R²⁸, and phenyl substituted with R²⁹.

115. The compound according to any one of clauses 1-113, wherein R²⁴ isselected from the group consisting of —C(═O)—R²⁶, —S(═O)₂—R²⁷,pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl substituted with R²⁸,and phenyl substituted with R²⁹.

116. The compound according to any one of clauses 1-115, wherein R²⁵ isselected from the group consisting of hydrogen, methyl, ethyl, isopropyland cyclopropyl.

117. The compound according to any one of clauses 1-115, wherein R²⁵ isselected from the group consisting of hydrogen, methyl, isopropyl andcyclopropyl.

118. The compound according to any one of clauses 1-117, wherein R¹²⁵ isselected from the group consisting of hydrogen, methyl, ethyl, isopropyland cyclopropyl.

119. The compound according to any one of clauses 1-118, wherein R¹²⁵ isselected from the group consisting of hydrogen, methyl, isopropyl andcyclopropyl.

120. The compound according to any one of clauses 1-119, wherein R⁴⁴ andR⁴⁵ are each independently selected from the group consisting hydrogen,fluorine, chlorine, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl,cyclohexyl and cyclopentyl, wherein said ethyl, isopropyl, cyclopropyl,cyclobutyl, cyclohexyl and cyclopentyl are optionally substituted withone substituent selected independently from the group consisting offluorine, chlorine, hydroxy and oxo.

121. The compound according to any one of clauses 1-119, wherein R⁴⁴ andR⁴⁵ are each independently selected from the group consisting hydrogen,fluorine, chlorine, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl,cyclohexyl and cyclopentyl, wherein said ethyl, cyclopropyl, cyclobutyl,cyclohexyl and cyclopentyl are optionally substituted with onesubstituent selected independently from the group consisting of fluorineand hydroxyl.

122. The compound according to any one of clauses 1-121, wherein R⁴⁴ andR⁴⁵ together with the carbon atom to which they are attached form acyclopropyl ring, wherein said ring are optionally substituted withhydroxy or fluorine.

123. The compound according to any one of clauses 1-122, wherein R⁴⁴ andR⁴⁵ together with the carbon atom to which they are attached form acyclobutyl ring, wherein said ring are optionally substituted withhydroxy or fluorine.

124. The compound according to any one of clauses 1-123, wherein R⁷⁰ andR⁷¹ are each independently selected from the group consisting hydrogen,fluorine, chlorine, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl,cyclohexyl and cyclopentyl, wherein said ethyl, isopropyl, cyclopropyl,cyclobutyl, cyclohexyl and cyclopentyl are optionally substituted withone substituent selected independently from the group consisting offluorine, chlorine, hydroxy and oxo.

125. The compound according to any one of clauses 1-123, wherein R⁷⁰ andR⁷¹ are each independently selected from the group consisting hydrogen,fluorine, chlorine, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl,cyclohexyl and cyclopentyl, wherein said ethyl, cyclopropyl, cyclobutyl,cyclohexyl and cyclopentyl are optionally substituted with onesubstituent selected independently from the group consisting of fluorineand hydroxyl.

126. The compound according to any one of clauses 1-123, wherein R⁷⁰ andR⁷¹ together with the carbon atom to which they are attached form acyclopropyl ring, wherein said ring are optionally substituted withhydroxy or fluorine.

127. The compound according to any one of clauses 1-123, wherein R⁷⁰ andR⁷¹ together with the carbon atom to which they are attached form acyclobutyl ring, wherein said ring are optionally substituted withhydroxy or fluorine.

128. The compound according to any one of clauses 1-123, wherein R⁷² andR⁷³ are each independently selected from the group consisting hydrogen,fluorine, chlorine, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl,cyclohexyl and cyclopentyl, wherein said ethyl, isopropyl, cyclopropyl,cyclobutyl, cyclohexyl and cyclopentyl are optionally substituted withone substituent selected independently from the group consisting offluorine, chlorine, hydroxy and oxo.

129. The compound according to any one of clauses 1-123, wherein R⁷² andR⁷³ are each independently selected from the group consisting hydrogen,fluorine, chlorine, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl,cyclohexyl and cyclopentyl, wherein said ethyl, cyclopropyl, cyclobutyl,cyclohexyl and cyclopentyl are optionally substituted with onesubstituent selected independently from the group consisting of fluorineand hydroxyl.

130. The compound according to any one of clauses 1-123, wherein R⁷² andR⁷³ together with the carbon atom to which they are attached form acyclopropyl ring, wherein said ring are optionally substituted withhydroxy or fluorine.

131. The compound according to any one clauses 1-123, wherein R⁷² andR⁷³ together with the carbon atom to which they are attached form acyclobutyl ring, wherein said ring are optionally substituted withhydroxy or fluorine.

132. The compound according to any one of clauses 1-131, wherein R³⁰ andR³¹ are each independently selected from the group consisting ofhydrogen, halogen, CN, —C(═O)OH, —C(═O)R⁴⁶, —CH(OH)—R⁴⁷, hydroxy,—(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)R⁴⁶,—(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹,—(CR⁴⁴—R⁴⁵)_(m)—C═C—R⁵¹R⁵², and —(CR⁴⁴R⁴⁵)_(m)—C≡C—R⁵³.

133. The compound according to any one of clauses 1-131, wherein R³⁰ andR³¹ are each independently selected from the group consisting ofhydrogen, halogen, CN, —C(═O)OH, hydroxy, —(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)R⁴⁶, —(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, and—(CR⁴⁴R⁴⁵)_(n)—C≡C—R⁵³.

134. The compound according to any one of clauses 1-131, wherein R³⁰ adR³¹ are each independently selected from the group consisting ofhydrogen, halogen, CN, —C(═O)OH, hydroxy, —C(═O)—NR⁴⁸R⁴⁹, —NR⁴⁸C(═O)R⁴⁶,—OR⁴⁹, —S(═O)₂R⁵⁰, —S(═O)₂NR⁴⁸R⁴⁹, —NR⁴⁸S(═O)₂R⁵⁰, —NR⁴⁸C(═O)—NR⁴⁸R⁴⁹and —C≡C—R⁵³.

135. The compound according to any one clauses 1-131, wherein R³⁰ ad R³¹are each independently selected from the group consisting of hydrogen,halogen, CN, —C(═O)OH, hydroxy, —C(═O)—NR⁴⁸R⁴⁹, —S(═O)₂R⁵⁰ and—S(═O)₂NR⁴⁸R⁴⁹.

136. The compound according to any one of clauses 1-131, wherein R³⁰ adR³¹ are each independently selected from the group consisting ofhydrogen, halogen, CN, —C(═O)OH, hydroxy, —NR⁴⁸C(═O)R⁴⁶, —OR⁴⁹,—NR⁴⁸S(═O)₂R⁵⁰ and —NR⁴⁸C(═O)—NR⁴⁸R⁴⁹.

137. The compound according to any one of clauses 1-131, wherein R³⁰ adR³¹ are each independently selected from the group consisting ofhydrogen, chlorine, fluorine, CN, —C(═O)OH, hydroxy, —NHC(═O)C₁₋₄alkyl,—OC₁₋₄alkyl, —OCH₂CH₂OH, —NHS(═O)₂C₁₋₄alkyl and —NHC(═O)—N(C₁₋₄alkyl)₂.

138. The compound according to any one of clauses 1-137, wherein R³⁰,R³¹, R⁴² and R⁴³ are each independently selected from the groupconsisting of —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀heterocyclyl substituted with R⁵⁴,—(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀cycloalkyl substituted with R⁵⁵,—(CR⁴⁴R⁴⁵)_(m)-aryl substituted with R⁵⁶ and R⁵⁷ and—(CR⁴⁴R⁴⁵)_(m)-heteroaryl substituted with R⁵⁶ and R⁵⁷.

139. The compound according to any one of clauses 1-137, wherein R³⁰,R³¹, R⁴² and R⁴³ are each independently selected from the groupconsisting of —C₃-C₁₀heterocyclyl substituted with R⁵⁴,—C₃-C₁₀cycloalkyl substituted with R⁵⁵, -phenyl substituted with R⁵⁶ andR⁵⁷ and -heteroaryl substituted with R⁵⁶ and R⁵⁷.

140. The compound according to any one of clauses 1-137, wherein R³⁰,R³¹, R⁴² and R⁴³ are each independently selected from the groupconsisting of tetrahydropyranyl, piperidinyl, pyrrolidinyl andmorpholinyl substituted with R⁵⁴, cyclopropyl, cyclobutyl, cyclohexyland cyclopentyl substituted with R⁵⁵, phenyl substituted with R⁵⁶ andR⁵⁷ and imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinylpyrimidinyl and pyridinyl substituted with R⁵⁶ and R⁵⁷.

141. The compound according to any one of clauses 1-137, wherein R³⁰,R³¹, R⁴² and R⁴³ are each independently selected from the groupconsisting of tetrahydropyranyl, piperidinyl, pyrrolidinyl andmorpholinyl substituted with R⁵⁴, cyclopropyl, cyclobutyl and cyclohexylsubstituted with R⁵⁵, phenyl substituted with R⁵⁶ and R⁵⁷ andpyridazinyl, pyrazinyl pyrimidinyl and pyridinyl substituted with R⁵⁶and R⁵⁷.

142. The compound according to any one of clauses 1-141, wherein R⁹⁰ andR⁹¹ are each independently selected from the group consisting ofhydrogen, halogen, ═O, —CN, —C(═O)OH, —C(═O)R⁴⁶, —CH(OH)—R⁴⁷, hydroxy,trifluoromethyl, —(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)R⁴⁶, —(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁰, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸R⁴⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—C═CR⁵¹R⁵², and—(CR⁴⁴R⁴⁵)_(m)—C≡C—R⁵³.

143. The compound according to any one of clauses 1-141, wherein R⁹⁰ andR⁹¹ are each independently selected from the group consisting ofhydrogen, fluorine, chlorine, ═O, —CN, —C(═O)OH, hydroxy,—(CR⁴⁴R⁴⁵)_(m)—C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)R⁴⁶,—(CR⁴⁴R⁴⁵)_(m)—OR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—SR⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—S(═O)₂R⁵⁰,—(CR⁴⁴R⁴⁵)_(m)—S(═O)₂NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸S(═O)₂R⁵⁹,—(CR⁴⁴R⁴⁵)_(m)—NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, —(CR⁴⁴R⁴⁵)_(m)—C═CR⁵¹R⁵², and—(CR⁴⁴R⁴⁵)_(m)—C≡C—R⁵³.

144. The compound according to any one of clauses 1-141, wherein R⁹⁰ andR⁹¹ are each independently selected from the group consisting ofhydrogen, fluorine, chlorine, —CN, —C(═O)OH, —NR⁴⁸C(═O)R⁴⁶,—NR⁴⁸S(═O)₂R⁵⁰ and —NR⁴⁸C(═O)—NR⁴⁸R⁴⁹.

145. The compound according to any one of clauses 1-141, wherein R⁹⁰ andR⁹¹ are each independently selected from the group consisting ofhydrogen, fluorine, chlorine, ═O, —CN, —C(═O)OH, —C(═O)—NR⁴⁸R⁴⁹, —OR⁴⁹,—SR⁴⁹, —S(═O)₂R⁵⁰, —S(═O)₂NR⁴⁸R⁴⁹, —C═CR⁵¹R⁵² and —C≡C—R⁵³.

146. The compound according to any one of clauses 1-141, wherein R⁹⁰ andR⁹¹ are each independently selected from the group consisting ofhydrogen, —(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀heterocyclyl substituted with R⁵⁴,—(CR⁴⁴R⁴⁵)_(m)—C₃-C₁₀cycloalkyl substituted with R⁵⁵,—(CR⁴⁴R⁴⁵)_(m)-aryl substituted with R⁵⁶ and R⁵⁷ and—(CR⁴⁴R⁴⁵)_(m)-heteroaryl substituted with R⁵⁶ and R⁵⁷.

147. The compound according to any one of clauses 1-141, wherein R⁹⁰ andR⁹¹ are each independently selected from the group consisting ofhydrogen, tetrahydropyranyl, piperidinyl, pyrrolidinyl and morpholinylsubstituted with R⁵⁴, cyclopropyl, cyclobutyl, cyclohexyl andcyclopentyl substituted with R⁵⁵, phenyl substituted with R⁵⁶ and R⁵⁷and -imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinylpyrimidinyl and pyridinyl substituted with R⁵⁶ and R⁵⁷.

148. The compound according to any one of clauses 1-141, wherein R⁹⁰ andR⁹¹ are each independently selected from the group consisting ofhydrogen, tetrahydropyranyl, piperidinyl and morpholinyl substitutedwith R⁵⁴, cyclopropyl, cyclobutyl and cyclohexyl substituted with R⁵⁵,phenyl substituted with R⁵⁶ and R⁵⁷ and pyridazinyl, pyrazinylpyrimidinyl and pyridinyl substituted with R⁵⁶ and R⁵⁷.

149. The compound according to any one of clauses 1-148, wherein m is 0.

150. The compound according to any one of clauses 1-148, wherein m is 1.

151. The compound according to any one of clauses 1-150, wherein R³²,R³³, R³⁷, R³⁸, R³⁹, R⁴⁰ and R⁴¹ are each independently selected from thegroup consisting of hydrogen, C₁-C₆alkyl and C₃-C₁₀cycloalkyl, whereinsaid C₁-C₆alkyl and C₃-C₁₀cycloalkyl are optionally substituted with oneor two independently selected R⁵⁸.

152. The compound according to clause 150, wherein R³², R³³, R³⁷, R³⁸,R³⁹, R⁴⁰ and R⁴¹ are each independently selected from the groupconsisting of hydrogen, C₁-C₆alkyl and C₃-C₁₀cycloalkyl, wherein saidC₁-C₆alkyl and C₃-C₁₀cycloalkyl are optionally substituted with one R⁵⁸.

153. The compound according to clause 150, wherein R³², R³³, R³⁷, R³⁸,R³⁹, R⁴⁰ and R⁴¹ are each independently selected from the groupconsisting of hydrogen, methyl, ethyl and isopropyl, trifluoromethyl andcyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl, wherein saidmethyl, ethyl and isopropyl, trifluoromethyl and cyclopropyl,cyclobutyl, cyclohexyl and cyclopentyl are optionally substituted withone R⁵⁸.

154. The compound according to clause 150, wherein R³², R³³, R³⁷, R³⁸,R³⁹, R⁴⁰ and R⁴¹ are each independently selected from the groupconsisting of hydrogen, C₃-C₁₀heterocyclyl, aryl and heteroaryl, whereinsaid C₃-C₁₀heterocyclyl, aryl and heteroaryl are optionally substitutedwith one or two independently selected R⁵⁸.

155. The compound according to clause 150, wherein R³², R³³, R³⁷, R³⁸,R³⁹, R⁴⁰ and R⁴¹ are each independently selected from the groupconsisting of hydrogen, C₃-C₁₀heterocyclyl, aryl and heteroaryl, whereinsaid C₃-C₁₀heterocyclyl, aryl and heteroaryl are optionally substitutedwith one or two independently selected R⁵⁸.

156. The compound according to clause 150, wherein R³², R³³, R³⁷, R³⁸,R³⁹, R⁴⁰ and R⁴¹ are each independently selected from the groupconsisting of hydrogen, tetrahydropyranyl, piperidinyl, pyrrolidinyl,morpholinyl, phenyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl,pyrazinyl, pyrimidinyl and pyridinyl wherein said tetrahydropyranyl,piperidinyl, pyrrolidinyl, morpholinyl, phenyl, imidazolyl, pyrazolyl,isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl areoptionally substituted with one or two independently selected R⁵⁸.

157. The compound according to clause 150, wherein R³², R³³, R³⁷, R³⁸,R³⁹, R⁴⁰ and R⁴¹ are each independently selected from the groupconsisting of hydrogen, tetrahydropyranyl, piperidinyl, morpholinyl,phenyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl wherein saidtetrahydropyranyl, piperidinyl, morpholinyl, phenyl, pyridazinyl,pyrazinyl, pyrimidinyl and pyridinyl are optionally substituted with oneR⁵⁸.

158. The compound according to any one of clauses 1-157, wherein R³⁴,R³⁵, and R³⁶ are each independently selected from the group consistingof hydrogen, C₁-C₆alkyl, C₃-C₁₀cycloalkyl and heteroaryl, wherein saidC₁-C₆alkyl, C₃-C₁₀cycloalkyl and heteroaryl are optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of halogen, methyl, ethyl and hydroxyl.

159. The compound according to any one clauses 1-158, wherein R³⁴ andR³⁵ together with the nitrogen to which they are attached form apiperidinyl, pyrrolidinyl and morpholinyl ring, wherein said ringoptionally is substituted with one or two substituents independentlyselected from the group consisting of hydroxy or fluorine.

160. The compound according to any one of clauses 1-157, wherein R³⁴,R³⁵, and R³⁶ are each independently selected from the group consistingof hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl,cyclohexyl, cyclopentyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl,pyrazinyl, pyrimidinyl and pyridinyl, wherein said methyl, ethyl,isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, imidazolyl,pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinylare optionally substituted with one, two or three substituentsindependently selected from the group consisting of fluorine, methyl,ethyl and hydroxyl.

161. The compound according to any one of clauses 1-157, wherein R³⁴,R³⁵, and R³⁶ are each independently selected from the group consistingof hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl,cyclohexyl, cyclopentyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl,pyrazinyl, pyrimidinyl and pyridinyl, wherein said methyl, ethyl,isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, imidazolyl,pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinylare optionally substituted with one substituent independently selectedfrom the group consisting of fluorine, methyl, ethyl and hydroxyl.

162. The compound according to any one of clauses 1-161, wherein R²⁶,R²⁷, R⁴⁶, R⁴⁷, R⁴⁹, R⁵⁰, R⁵¹, R⁵³ and R⁵² are each independentlyselected from the group consisting of hydrogen, C₁-C₆alkyl, heteroaryland C₃-C₁₀cycloalkyl, wherein said C₁-C₆alkyl, heteroaryl andC₃-C₁₀cycloalkyl are optionally substituted with one, two or threesubstituents independently selected from the group consisting ofhalogen, methyl, ethyl, methoxy, ethoxy, —OCH₂CH₂OH, carboxy andhydroxy.

163. The compound according to any one of clauses 1-162, wherein R⁵⁴,R⁵⁵, R⁵⁶ and R⁵⁷ are each independently selected from the groupconsisting of hydrogen, C₁-C₆alkyl, heteroaryl and C₃-C₁₀cycloalkyl,wherein said C₁-C₆alkyl, heteroaryl and C₃-C₁₀cycloalkyl are optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of halogen, methyl, ethyl, methoxy, ethoxy,—OCH₂CH₂OH, carboxy and hydroxy.

164. The compound according to any one of clauses 1-163, wherein R²⁶,R²⁷, R⁴⁶, R⁴⁷, R⁴⁹, R⁵⁰, R⁵¹, R⁵³ and R⁵² are each independentlyselected from the group consisting of hydrogen, methyl, ethyl,isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, imidazolyl,pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl andpyridinyl, wherein said methyl, ethyl, isopropyl, cyclopropyl,cyclobutyl, cyclohexyl, cyclopentyl, imidazolyl, pyrazolyl, isoxazolyl,pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl are optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of fluorine, chlorine, methyl, ethyl, methoxy,ethoxy, —OCH₂CH₂OH, carboxy and hydroxy.

165. The compound according to any one of clauses 1-164, wherein R⁵⁴,R⁵⁵, R⁵⁶ and R⁵⁷ are each independently selected from the groupconsisting of hydrogen, halogen, —CN, trifluoromethyl, —OCH₂CH₂OH,hydroxyl.

166. The compound according to any one of clauses 1-164, wherein R⁵⁴,R⁵⁵, R⁵⁶ and R⁵⁷ are each independently selected from the groupconsisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl,cyclobutyl, cyclohexyl, cyclopentyl, imidazolyl, pyrazolyl, isoxazolyl,pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl, wherein said methyl,ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyland pyridinyl are optionally substituted with one, two or threesubstituents independently selected from the group consisting offluorine, chlorine methyl, ethyl, methoxy, ethoxy, —OCH₂CH₂OH, carboxyand hydroxy.

167. The compound according to any one of clauses 1-166, wherein R⁴⁸ isselected from the group consisting of hydrogen, methyl, ethyl andisopropyl, tetrahydropyrane, cyclohexyl and cyclopentyl wherein saidmethyl, ethyl and isopropyl, tetrahydropyrane, cyclohexyl andcyclopentyl are optionally substituted with one or two substituentsindependently selected from the group consisting of fluorine andhydroxy.

168. The compound according to any one of clauses 1-167, wherein R⁴⁹ isselected from the group consisting of hydrogen, methyl, ethyl andisopropyl, tetrahydropyrane, cyclohexyl and cyclopentyl wherein saidmethyl, ethyl and isopropyl, tetrahydropyrane, cyclohexyl andcyclopentyl are optionally substituted with one or two substituentsindependently selected from the group consisting of fluorine andhydroxy.

169. The compound according to any one of clauses 1-167, wherein R⁴⁹ isH and R⁴⁸ is selected from the group consisting of hydrogen, methyl,ethyl and isopropyl, tetrahydropyrane, cyclohexyl and cyclopentylwherein said methyl, ethyl and isopropyl, tetrahydropyrane, cyclohexyland cyclopentyl are optionally substituted with one or two substituentsindependently selected from the group consisting of fluorine andhydroxy.

170. The compound according to any one of clauses 1-167, wherein R⁴⁸ isH and R⁴⁹ is selected from the group consisting of hydrogen, methyl,ethyl and isopropyl, tetrahydropyrane, cyclohexyl and cyclopentylwherein said methyl, ethyl and isopropyl, tetrahydropyrane, cyclohexyland cyclopentyl are optionally substituted with one or two substituentsindependently selected from the group consisting of fluorine andhydroxy.

171. The compound according to any one of clauses 1-167, wherein R⁴⁸ andR⁴⁹ together with the nitrogen to which they are attached form apiperidinyl, pyrrolidinyl and morpholinyl ring, wherein said ringoptionally is substituted with one or two substituents independentlyselected from the group consisting of hydroxy and fluoride.

172. The compound according to any one of clauses 1-171, wherein R⁵⁸ areeach independently selected from selected from the group consisting ofhalogen, —CN, hydroxy, oxo, —C(═O)OH, —S(═O)₂R⁵⁹, —S—NR⁶⁰R⁶¹,S(═O)₂NR⁶⁰R⁶¹, cyclopropyl, —OR⁵⁹, —SR⁹, C₁-C₆alkyl, —C(═O)NR⁶⁰R⁶¹,—NR⁶⁰C(═O)NR⁶¹R⁶⁰, —NR⁶⁰S(═O)₂R⁵⁹ and —NC(═O)R⁵⁹.

173. The compound according to any one of clauses 1-171, wherein R⁵⁸ isselected from the group consisting of fluorine, chlorine, —CN, hydroxy,oxo, —C(═O)OH, —S(═O)₂R⁵⁹, —S(═O)₂NR⁶⁰R⁶¹, cyclopropyl, —OR⁵⁹, —SR⁵⁹,methyl, ethyl, isopropyl, —C(═O)NR⁶⁰R⁶¹, —NR⁶⁰C(═O)NR⁶¹R⁶⁰,—NR⁶⁰S(═O)₂R⁵⁹ and —NC(═O)R⁵⁹.

174. The compound according to any one of clauses 1-171, wherein R⁵⁸ areeach independently selected from selected from the group consisting offluorine, chlorine, —CN, hydroxy, oxo, —C(═O)OH, —S(═O)₂R⁵⁹,cyclopropyl, —OR⁵⁹, methyl, ethyl, isopropyl and —C(═O)NR⁶⁰R⁶¹.

175. The compound according to any one of clauses 1-171, wherein R⁵⁸ areeach independently selected from selected from the group consisting of—S(═O)₂NR⁶⁰R⁶¹, —SR⁵⁹, —NR⁶⁰C(═O)NR⁶¹R⁶⁰, —NR⁶⁰S(═O)₂R⁵⁹ and —NC(═O)R⁵⁹.

176. The compound according to any one of clauses 1-175, wherein R⁵⁹ isselected from the group consisting of hydrogen, C₁-C₆alkyl andC₃-C₁₀cycloalkyl wherein said —C₆alkyl, C₃-C₁₀cycloalkyl are optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of halogen, methyl, ethyl, methoxy, ethoxytrifluoromethyl and hydroxy.

177. The compound according to any one of clauses 1-175, wherein R⁵⁹ isselected from the group consisting of hydrogen, phenyl and heteroaryl,wherein said, phenyl and heteroaryl are optionally substituted with one,two or three substituents independently selected from the groupconsisting of halogen, methyl, ethyl, methoxy, ethoxy and hydroxy.

178. The compound according to any one of clauses 1-175, wherein R⁵⁹ isselected from the group consisting of hydrogen, methyl, ethyl andisopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl,imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyland pyridinyl, wherein said methyl, ethyl and isopropyl, cyclopropyl,cyclobutyl, cyclohexyl, cyclopentyl, phenyl, imidazolyl, pyrazolyl,isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl areoptionally substituted with one, two or three substituents independentlyselected from the group consisting of halogen, methyl, ethyl, methoxy,ethoxy and hydroxy.

179. The compound according to any one of clauses 1-178, wherein R⁶⁰ areeach independently selected from the group consisting of hydrogen,methyl, ethyl, isopropyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl,morpholinyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, andheteroaryl, wherein said methyl, ethyl, isopropyl, tetrahydropyranyl,piperidinyl, pyrrolidinyl, morpholinyl, cyclopropyl, cyclobutyl,cyclohexyl, cyclopentyl, and heteroaryl are optionally substituted withone or two substituents independently selected from the group consistingof fluorine, chlorine and hydroxy.

180. The compound according to any one of clauses 1-178, wherein R⁶⁰ areeach independently selected from the group consisting of hydrogen,methyl, ethyl, isopropyl, cyclopropyl, wherein said methyl, ethyl,isopropyl and cyclopropyl are optionally substituted with one or twosubstituents independently selected from the group consisting offluorine, chlorine and hydroxy.

181. The compound according to any one of clauses 1-180, wherein R⁶¹ areeach independently selected from the group consisting of hydrogen,C₁-C₆alkyl, C₃-C₁₀heterocyclyl, C₃-C₁₀cycloalkyl and heteroaryl, whereinsaid C₁-C₆alkyl, C₃-C₁₀heterocyclyl, C₃-C₁₀cycloalkyl and heteroaryl areoptionally substituted with one or two substituents independentlyselected from the group consisting of halogen and hydroxy.

182. The compound according to any one clauses 1-181, wherein R⁶¹ areeach independently selected from the group consisting of hydrogen,methyl, ethyl, isopropyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl,morpholinyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, andheteroaryl, wherein said methyl, ethyl, isopropyl, tetrahydropyranyl,piperidinyl, pyrrolidinyl, morpholinyl, cyclopropyl, cyclobutyl,cyclohexyl, cyclopentyl, and heteroaryl are optionally substituted withone or two substituents independently selected from the group consistingof fluorine, chlorine and hydroxy.

183. The compound according to any one of clauses 1-182, wherein R⁹³ isselected from the group consisting of hydrogen, methyl, ethyl,isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl,imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyland pyridinyl, wherein said methyl, ethyl, isopropyl, cyclopropyl,cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl,pyrrolidinyl, morpholinyl, phenyl, imidazolyl, pyrazolyl, isoxazolyl,pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl are optionallysubstituted with one, two or three independently selected R⁵⁸.

184. The compound according to any one of clauses 1-182, wherein R⁹³ isselected from the group consisting of hydrogen, methyl, ethyl,isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,tetrahydropyranyl, piperidinyl, morpholinyl, phenyl, pyrimidinyl andpyridinyl, wherein said methyl, ethyl, isopropyl, cyclopropyl,cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl,morpholinyl, phenyl, pyrimidinyl and pyridinyl are optionallysubstituted with one, two or three independently selected R⁵⁸.

185. The compound according to any one of clauses 1-184, wherein R⁹⁴ andR⁹⁵ are each independently selected from the group consisting ofhydrogen, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, imidazolyl,pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl andpyridinyl, wherein said cyclopropyl, cyclobutyl, cyclohexyl,cyclopentyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl,pyrimidinyl and pyridinyl are optionally substituted with one, two orthree substituents independently selected from the group consisting offluorine, chlorine, methyl, ethyl and hydroxy.

186. The compound according to any one of clauses 1-184, wherein R⁹⁴ ishydrogen and R⁹⁵ are selected from the group consisting of hydrogen,cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, imidazolyl, pyrazolyl,isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl, whereinsaid cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, imidazolyl,pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinylare optionally substituted with one, two or three substituentsindependently selected from the group consisting of fluorine, chlorine,methyl, ethyl and hydroxy.

187. The compound according to any one of clauses 1-184, wherein R⁹⁴ andR⁹⁵ together with the nitrogen to which they are attached form apiperidinyl, pyrrolidinyl and morpholinyl ring, wherein said ringoptionally is substituted with one or two substituents independentlyselected from the group consisting of hydroxy or fluorine.

188. The compound according to any one of clauses 1-184, wherein R⁹⁴ andR⁹⁵ together with the nitrogen to which they are attached form apiperidinyl and pyrrolidinyl ring, wherein said ring optionally issubstituted with one or two substituents independently selected from thegroup consisting of hydroxy or fluorine.

189. The compound according to any one of clauses 1-188, wherein R⁶² isselected from the group consisting of fluoride, chloride, —C(═O)OH,—CH(OH)—R⁴⁷, —C(═O)—NR⁴⁸R⁴⁹, —NR⁴⁸C(═O)R⁴⁶, —SR⁴⁹, —S(═O)₂R⁵⁰,—S(═O)₂NR⁴⁸R⁴⁹, —NR⁴⁸S(═O)₂R⁵⁰, —NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, —C═C—R⁵¹R⁵²,—C≡C—R⁵³, and CH₂CH₂OH, —CH₂CH₂OH.

190. The compound according to any one of clauses 1-188, wherein R⁶² isselected from the group consisting of C₃-C₁₀heterocyclyl substitutedwith R⁵⁴, C₃-C₁₀cycloalkyl substituted with R⁵⁵, aryl substituted withR⁵⁶ and R⁵⁷ and heteroaryl substituted with R⁵⁶ and R⁵⁷.

191. The compound according to any one clauses 1-188, wherein R⁶² isselected from the group consisting of fluorine, chlorine,—CH(OH)-cyclopropyl, —C(═O)—NR⁴⁸R⁴⁹, —NR⁴⁸C(═O)R⁴⁶, —S(═O)₂R⁵⁰,—S(═O)₂NR⁴⁸R⁴⁹, —NR⁴⁸S(═O)₂R⁵⁰, —NR⁴⁸C(═O)—NR⁴⁸R⁴⁹, CH₂CH₂OH, —CH₂CH₂OH.

192. The compound according to any one of clauses 1-188, wherein R⁶² isselected from the group consisting of tetrahydropyranyl, piperidinyl,pyrrolidinyl, morpholinyl substituted with R⁵⁴, cyclopropyl, cyclobutyl,cyclohexyl, cyclopentyl substituted with R⁵⁵, phenyl substituted withR⁵⁶ and R⁵⁷ and imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl,pyrazinyl, pyrimidinyl and pyridinyl substituted with R⁵⁶ and R⁵⁷.

193. The compound according to any one of clauses 1-192, wherein R⁶³ isselected from the group consisting of hydrogen, fluoride, chloride,hydroxy, oxo, —S(═O)₂R⁵⁹, —S(═O)₂NR⁶⁰R⁶¹, —S(═O)NR⁶⁰R⁶¹ cyclopropyl,—OR⁵⁹, methyl, ethyl, isopropyl, —C(═O)NR⁶⁰R⁶¹, —NR⁶⁰C(═O)NR⁶¹R⁶⁰;—NR⁶⁰S(═O)₂R⁵⁹, and —N(C═O)R⁵⁹.

194. The compound according to any one of clauses 1-192, wherein R⁶³ isselected from the group consisting of hydrogen, fluoride, chloride,hydroxy, oxo, —S(═O)₂R⁵⁹, —S(═O)₂NR⁶⁰R⁶¹, —S(═O)NR⁶⁰R⁶¹ cyclopropyl,—OR⁵⁹, methyl, ethyl, isopropyl and —C(═O)NR⁶⁰R⁶¹.

195. The compound according to any one of clauses 1-192, wherein R⁶³ isselected from the group consisting of hydrogen, fluoride, chloride,trifluoromethyl, hydroxy, oxo, —S(═O)₂cyclopropyl, —S(═O)₂methyl,cyclopropyl, —OR⁵⁹, methyl, ethyl and isopropyl.

196. A compound according to any one of clauses 1-195, wherein saidcompound is selected from the group consisting ofN-(5-Hydroxy-adamantan-2-yl)-N-methyl-3-phenethyloxy-benzamide,N-(5-Hydroxy-adamantan-2-yl)-3-phenethyloxy-benzamide,3-Cyclohexylmethoxy-N-(5-hydroxy-adamantan-2-yl)-N-methyl-benzamide,N-(5-Hydroxy-adamantan-2-yl)-N-methyl-3-(1-methyl-butoxy)-benzamide,N-(5-Hydroxy-adamantan-2-yl)-3-methoxy-N-methyl-benzamide,N-(5-Hydroxy-adamantan-2-yl)-N-methyl-3-(2-pyridin-2-yl-ethoxy)-benzamide,N-(5-Hydroxy-adamantan-2-yl)-3-(2-pyridin-2-yl-ethoxy)-benzamide,3-Benzyloxy-N-(5-hydroxy-adamantan-2-yl)-benzamide,N-(5-Hydroxy-adamantan-2-yl)-3-(2-morpholin-4-yl-ethoxy)-benzamide,4-{2-[3-(5-Hydroxy-adamantan-2-ylcarbamoyl)-phenoxy]-ethyl}-piperidine-1-carboxylicacid isopropylamide,3-[2-(1-Cyclopropanesulfonyl-piperidin-4-yl)-ethoxy]-N-(5-hydroxy-adamantan-2-yl)-benzamide,3-(6-Chloro-pyridin-3-ylmethoxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide,N-(5-Hydroxy-adamantan-2-yl)-3-(tetrahydro-pyran-4-ylmethoxy)-benzamide,N-(5-Hydroxy-adamantan-2-yl)-3-[2-(tetrahydro-pyran-4-yl)-ethoxy]-benzamide,N-(5-Hydroxy-adamantan-2-yl)-3-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-benzamide,N-(5-Hydroxy-adamantan-2-yl)-N-methyl-3-(tetrahydro-pyran-4-yloxy)-benzamide′,(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-[3-(tetrahydro-pyran-4-ylmethoxy)-phenyl]-methanone,(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-{3-[2-(tetrahydro-pyran-4-yl)-ethoxy]-phenyl}-methanone,(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-[3-(4-hydroxy-cyclohexylmethoxy)-phenyl]-methanone.

197. A compound according to any one of clauses 1-196, which is an agentuseful for the treatment, prevention and/or prophylaxis of anyconditions, disorders and diseases wherein a modulation or an inhibitionof the activity of 11βHSD1 is beneficial.

198. A compound according to any one of the clauses 1-196, which is anagent useful for the treatment, prevention and/or prophylaxis of anyconditions, disorders and diseases that are influenced by intracellularglucocorticoid levels.

199. A compound according to any one of the clauses 1-196, which is anagent useful for the treatment, prevention and/or prophylaxis ofconditions, disorders or diseases selected from the group consisting ofthe metabolic syndrome, insulin resistance, dyslipidemia, hypertensionand obesity.

200. A compound according to any one of the clauses 1-196, which is anagent useful for the treatment, prevention and/or prophylaxis of type 2diabetes, impaired glucose tolerance (IGT), impaired fasting glucose(IFG).

201. A compound according to any one of the clauses 1-196, which is anagent useful for the delaying or prevention of the progression from IGTinto type 2 diabetes.

202. A compound according to any one of the clauses 1-196, which is anagent useful for delaying or prevention of the progression of themetabolic syndrome into type 2 diabetes.

203. A compound according to any one of the clauses 1-196, which is anagent useful for the treatment, prevention and/or prophylaxis of adverseeffects of glucocorticoid receptor agonist treatment or therapy.

204. A pharmaceutical composition comprising, as an active ingredient,at least one compound according to any one of the clauses 1-196 togetherwith one ore more pharmaceutically acceptable carriers or excipients.

205. The pharmaceutical composition according to clause 204 which is fororal, nasal, buccal, transdermal, pulmonal or parenteral administration.

206. The pharmaceutical composition according to clause 204 or 205 inunit dosage form, comprising from 0.05 mg to 2000 mg/day, from 0.1 mg to1000 mg or from 0.5 mg to 500 mg per day of the compound according toanyone of the clauses 1-196.

207. A use of a compound according to any of the clauses 1-196, for thepreparation of a pharmaceutical composition for the treatment,prevention and/or prophylaxis of any conditions, disorders and diseaseswherein a modulation or an inhibition of the activity of 11βHSD1 isbeneficial.

208. A use of a compound according to any of the clauses 1-196, for thepreparation of a pharmaceutical composition for the treatment,prevention and/or prophylaxis of any conditions, disorders and diseasesthat are influenced by intracellular glucocorticoid levels.

209. A use of a compound according to any of the clauses 1-196, for thepreparation of a pharmaceutical composition for the treatment,prevention and/or prophylaxis of conditions, disorders or diseasesselected from the group consisting of the metabolic syndrome, insulinresistance, dyslipidemia, hypertension and obesity.

210. A use of a compound according to any of the clauses 1-196, for thepreparation of a pharmaceutical composition for the treatment,prevention and/or prophylaxis of type 2 diabetes, impaired glucosetolerance (IGT), impaired fasting glucose (IFG).

211. A use of a compound according to any of the clauses 1-196, for thepreparation of a pharmaceutical composition for the delaying orprevention of the progression from IGT to type 2 diabetes.

212. A use of a compound according to any of the clauses 1-196, for thepreparation of a pharmaceutical composition for the delaying orprevention of the progression of the metabolic syndrome into type 2diabetes.

213. A use of a compound according to any of the clauses 1-196, for thepreparation of a pharmaceutical composition for the treatment,prevention and/or prophylaxis of adverse effects of glucocorticoidreceptor agonist treatment or therapy.

214. A method for the treatment, prevention and/or prophylaxis of anyconditions, disorders or diseases wherein a modulation or an inhibitionof the activity of 11βHSD1 is beneficial, the method comprisingadministering to a subject in need thereof an effective amount of acompound according to any one of clauses 1-196.

215. The method according to clause 214 wherein the conditions,disorders or diseases are selected from the group consisting of themetabolic syndrome, insulin resistance, dyslipidemia, hypertension andobesity.

The invention claimed is:
 1. A method of treating of glaucoma comprisingadministering to a subject in need thereof an effective amount of acompound, wherein the compound is a compound of Formula (I) or apharmaceutically acceptable salt thereof:

wherein: R¹ is hydrogen; R² is 5-hydroxy-adamantan-2-yl; R⁴ is hydrogen;R⁵ is hydrogen; and Y is selected from the group consisting of2-[1-(carboxylic acid isopropylamide)-piperidin-4-yl]-ethoxy,6-chloro-pyridin-3-ylmethoxy, tetrahydropyran-4-ylmethoxy,2-(2-oxo-pyrrolidin-1-yl)-ethoxy, 5-chloro-pyridin-2-yloxy,6-bromo-pyridin-3-yloxy, phenethyloxy, 2-(tetrahydropyran-4-yl)-ethoxy,benzyloxy, 2-(1-cyclopropane-sulfonyl-piperidin-4-yl)-ethoxy, and4-fluorobenzyloxy.
 2. The method of claim 1, wherein the compound is4-{2-[3-(5-Hydroxy-adamantan-2-ylcarbamoyl)-phenoxy]-ethyl}-piperidine-1-carboxylicacid isopropylamide or a pharmaceutically acceptable salt thereof. 3.The method of claim 1, wherein the compound is3-(6-Chloro-pyridin-3-ylmethoxy)-N-(5-hydroxy-adamantan-2-yl)-benzamideor a pharmaceutically acceptable salt thereof.
 4. The method of claim 1,wherein the compound isN-(5-Hydroxy-adamantan-2-yl)-3-(tetrahydro-pyran-4-ylmethoxy)-benzamideor a pharmaceutically acceptable salt thereof.
 5. The method of claim 1,wherein the compound isN-(5-Hydroxy-adamantan-2-yl)-3-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-benzamideor a pharmaceutically acceptable salt thereof.
 6. The method of claim 1,wherein the compound is3-(5-Chloro-pyridin-2-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide or apharmaceutically acceptable salt thereof.
 7. The method of claim 1,wherein the compound is3-(6-Bromo-pyridin-3-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide or apharmaceutically acceptable salt thereof.
 8. The method of claim 1,wherein the compound isN-(5-Hydroxy-adamantan-2-yl)-3-phenethyloxy-benzamide or apharmaceutically acceptable salt thereof.
 9. The method of claim 1,wherein the compound isN-(5-Hydroxy-adamantan-2-yl)-3-[2-(tetrahydro-pyran-4-yl)-ethoxy]-benzamideor a pharmaceutically acceptable salt thereof.
 10. The method of claim1, wherein the compound is3-Benzyloxy-N-(5-hydroxy-adamantan-2-yl)-benzamide or a pharmaceuticallyacceptable salt thereof.
 11. The method of claim 1, wherein the compoundis3-[2-(1-Cyclopropane-sulfonyl-piperidin-4-yl)-ethoxy]-N-(5-hydroxy-adamantan-2-yl)-benzamideor a pharmaceutically acceptable salt thereof.
 12. The method of claim1, wherein the compound is3-(4-Fluoro-benzyloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide or apharmaceutically acceptable salt thereof.
 13. A method of treatingdysregulation of intraocular pressure comprising administering to asubject in need thereof an effective amount of a compound, wherein thecompound is a compound of Formula (I) or a pharmaceutically acceptablesalt thereof:

wherein: R¹ is hydrogen; R² is 5-hydroxy-adamantan-2-yl; R⁴ is hydrogen;R⁵ is hydrogen; and Y is selected from the group consisting of2-[1-(carboxylic acid isopropylamide)-piperidin-4-yl]-ethoxy,6-chloro-pyridin-3-ylmethoxy, tetrahydropyran-4-ylmethoxy,2-(2-oxo-pyrrolidin-1-yl)-ethoxy, 5-chloro-pyridin-2-yloxy,6-bromo-pyridin-3-yloxy, phenethyloxy, 2-(tetrahydropyran-4-yl)-ethoxy,benzyloxy, 2-(1-cyclopropane-sulfonyl-piperidin-4-yl)-ethoxy, and4-fluorobenzyloxy.
 14. The method of claim 13, wherein the compound is4-{2-[3-(5-Hydroxy-adamantan-2-ylcarbamoyl)-phenoxy]-ethyl}-piperidine-1-carboxylicacid isopropylamide or a pharmaceutically acceptable salt thereof. 15.The method of claim 13, wherein the compound is3-(6-Chloro-pyridin-3-ylmethoxy)-N-(5-hydroxy-adamantan-2-yl)-benzamideor a pharmaceutically acceptable salt thereof.
 16. The method of claim13, wherein the compound isN-(5-Hydroxy-adamantan-2-yl)-3-(tetrahydro-pyran-4-ylmethoxy)-benzamideor a pharmaceutically acceptable salt thereof.
 17. The method of claim13, wherein the compound isN-(5-Hydroxy-adamantan-2-yl)-3-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-benzamideor a pharmaceutically acceptable salt thereof.
 18. The method of claim13, wherein the compound is3-(5-Chloro-pyridin-2-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide or apharmaceutically acceptable salt thereof.
 19. The method of claim 13,wherein the compound is3-(6-Bromo-pyridin-3-yloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide or apharmaceutically acceptable salt thereof.
 20. The method of claim 13,wherein the compound isN-(5-Hydroxy-adamantan-2-yl)-3-phenethyloxy-benzamide or apharmaceutically acceptable salt thereof.
 21. The method of claim 13,wherein the compound isN-(5-Hydroxy-adamantan-2-yl)-3-[2-(tetrahydro-pyran-4-yl)-ethoxy]-benzamideor a pharmaceutically acceptable salt thereof.
 22. The method of claim13, wherein the compound is3-Benzyloxy-N-(5-hydroxy-adamantan-2-yl)-benzamide or a pharmaceuticallyacceptable salt thereof.
 23. The method of claim 13, wherein thecompound is3-[2-(1-Cyclopropane-sulfonyl-piperidin-4-yl)-ethoxy]-N-(5-hydroxy-adamantan-2-yl)-benzamideor a pharmaceutically acceptable salt thereof.
 24. The method of claim13, wherein the compound is3-(4-Fluoro-benzyloxy)-N-(5-hydroxy-adamantan-2-yl)-benzamide or apharmaceutically acceptable salt thereof.